Cochrane Report

Non-steroid agents for idiopathic pulmonary fibrosis (Review)

Spagnolo P, Del Giovane C, Luppi F, Cerri S, Balduzzi S, Walters EH, D’Amico R, Richeldi L

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2010, Issue 9

http://www.thecochranelibrary.com

Non-steroid agents for idiopathic pulmonary fibrosis (Review)

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

4METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26

Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27

Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28

29DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

31AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

32REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

38CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

62DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Interferon gamma-1beta versus placebo, Outcome 1 Overall survival. . . . . . . . 64

Analysis 1.2. Comparison 1 Interferon gamma-1beta versus placebo, Outcome 2 Progression-free survival. . . . . 64

Analysis 2.1. Comparison 2 Pirfenidone versus placebo, Outcome 1 Progression-free survival. . . . . . . . . 65

Analysis 2.2. Comparison 2 Pirfenidone versus placebo, Outcome 2 Absolute change VC from baseline. . . . . . 65

Analysis 3.1. Comparison 3 Azathioprine & prednisone versus prednisone, Outcome 1 Overall survival. . . . . . 66

Analysis 3.2. Comparison 3 Azathioprine & prednisone versus prednisone, Outcome 2 % Predicted change FVC at 12

months. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 66

Analysis 4.1. Comparison 4 Colchicine versus prednisone, Outcome 1 Progression-free survival. . . . . . . . 67

Analysis 4.2. Comparison 4 Colchicine versus prednisone, Outcome 2 % Predicted change FVC at 3 months. . . . 67

Analysis 5.1. Comparison 5 N-Acetylcysteine & prednisone & azathioprine versus prednisone & azathioprine & placebo,

Outcome 1 Overall survival. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68

Analysis 5.2. Comparison 5 N-Acetylcysteine & prednisone & azathioprine versus prednisone & azathioprine & placebo,

Outcome 2 Absolute change VC from baseline at 12 months. . . . . . . . . . . . . . . . . . 68

Analysis 6.1. Comparison 6 Anticoagulant therapy & prednisolone versus prednisolone, Outcome 1 Overall survival. 69

Analysis 7.1. Comparison 7 Etanercept versus placebo, Outcome 1 Progression-free survival. . . . . . . . . . 69

Analysis 7.2. Comparison 7 Etanercept versus placebo, Outcome 2 % Predicted change FVC at 48 weeks. . . . . 70

Analysis 8.1. Comparison 8 Imatinib versus placebo, Outcome 1 Progression-free survival. . . . . . . . . . 70

Analysis 8.2. Comparison 8 Imatinib versus placebo, Outcome 2 Overall survival. . . . . . . . . . . . . 71

Analysis 8.3. Comparison 8 Imatinib versus placebo, Outcome 3 % Predicted change FVC at 96 weeks. . . . . . 71

Analysis 9.1. Comparison 9 Bosentan versus placebo, Outcome 1 Progression-free survival. . . . . . . . . . 72

72WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

72CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

73NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

73INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iNon-steroid agents for idiopathic pulmonary fibrosis (Review)


[Intervention Review]

Non-steroid agents for idiopathic pulmonary fibrosis

Paolo Spagnolo1 , Cinzia Del Giovane2 , Fabrizio Luppi3, Stefania Cerri1, Sara Balduzzi2 , E. Haydn Walters4, Roberto D’Amico2, Luca

Richeldi1

1Center for Rare Lung Disease, University of Modena and Reggio Emilia, Modena Italy and Respiratory Disease Section, Department of

Oncology, Hematology and Respiratory Disease, University of Modena and Reggio Emilia, Modena, Italy. 2Statistics Unit, Department

of Oncology, Hematology and Respiratory Disease, University of Modena and Reggio Emilia, Modena, Italy. 3Center for Rare Lung

Disease, University of Modena and Reggio Emilia, Modena Italy and Respiratory Disease Section, Department of Oncology, Hematology

and Respiratory Disease Azienda Ospedaliero-Universitaria di Modena, Modena, Italy. 4Menzies Research Institute, University of

Tasmania, Hobart, Australia

Contact address: Luca Richeldi, Center for Rare Lung Disease, University of Modena and Reggio Emilia, Via del Pozzo, 71, Modena,

41100, Italy. [email protected].

Editorial group: Cochrane Airways Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 9, 2010.

Review content assessed as up-to-date: 26 July 2010.

Citation: Spagnolo P, Del Giovane C, Luppi F, Cerri S, Balduzzi S, Walters EH, D’Amico R, Richeldi L. Non-steroid

agents for idiopathic pulmonary fibrosis. Cochrane Database of Systematic Reviews 2010, Issue 9. Art. No.: CD003134. DOI:

10.1002/14651858.CD003134.pub2.


A B S T R A C T

Background

Idiopathic pulmonary fibrosis is a chronic progressive lung disease with poor outcome and no effective treatment to date. This is an

update of a Cochrane Review first published in 2003.

Objectives

To assess the efficacy of non-steroid agents in adults with idiopathic pulmonary fibrosis.

Search strategy

We searched the Cochrane Airways Group Register (30 March 2010), the Cochrane Central Register of Controlled Trials (CENTRAL)

(The Cochrane Library, Issue 1, 2010), Ovid MEDLINE to March week 5, 2010, EMBASE to week 13, 2010 and PubMed to April

2010, with additional handsearching, including abstracts of international conferences. We also contacted pharmaceutical companies

and researchers in the field.

Selection criteria

Randomised studies comparing non-steroid drugs with placebo or steroids in adults with idiopathic pulmonary fibrosis.

Data collection and analysis

Two authors independently assessed trial quality, extracted data and assessed risk of bias. We contacted pharmaceutical companies to

obtain missing information, if any. We combined survival outcomes using Peto odds ratios or hazard ratios (HR).

1Non-steroid agents for idiopathic pulmonary fibrosis (Review)


mailto:[email protected]

Main results

Fifteen trials involving 10 different drugs were included. Two trials enrolling 1156 patients compared interferon gamma-1beta with

placebo: interferon gamma-1beta did not significantly improve survival (HR 0.88, 95% CI 0.47 to 1.64; P = 0.68). Four trials involving

1155 patients compared pirfenidone with placebo. Three trials, conducted in 1046 patients, provided data on progression-free survival:

pirfenidone significantly reduced the risk of disease progression by 30% (HR 0.70, 95% CI 0.56 to 0.88, P = 0.002). Data on the

effect of pirfenidone on pulmonary function could only be assessed for two studies analysing 314 patients. Forced vital capacity or vital

capacity was significantly improved by pirfenidone (mean difference 0.08 L, 95% CI 0.03 to 0.13, P = 0.0006).

Authors’ conclusions

Based on available data, partly still unpublished, pirfenidone appears to improve progression-free survival and, to a lesser extent,

pulmonary function in patients with idiopathic pulmonary fibrosis. More data are needed on overall survival and quality of life on

treatment. From the studies in this review, interferon gamma-1beta has not been shown to affect survival. Other agents evaluated in

single studies either failed to provide evidence for a benefit or need to be assessed in larger randomised controlled trials.

P L A I N L A N G U A G E S U M M A R Y

Non-steroid agents for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a form of progressive lung disease which ultimately leads to death. The cause is unknown, but the disease

is characterised by scar tissue in the lungs. This prevents the lungs from working effectively. Standard treatment uses oral corticosteroids

in association with immunosuppressors, but there is uncertainty as to whether this treatment is effective. Immunosuppressive agents

such as azathioprine and cyclophosphamide have been used to treat the disease because it is thought they might prevent inflammation.

The review found 15 high quality trials of non-steroid drugs tested in idiopathic pulmonary fibrosis patients. Notwithstanding the

encouraging results of a first small study included in the first version of this review, the effects of interferon gamma-1beta, as assessed

by combining two subsequent large trials, were disappointing and failed to show an effect on improving survival. Four studies did

evaluate pirfenidone, an anti-fibrotic oral drug, on a large number of patients: although two of these studies have only been presented

in conferences,combining the published and unpublished data showed a significant improvement of pirfenidone on progression-free

survival and a small increase in pulmonary function. Current evidence suggests a possible role for pirfenidone in the treatment of

idiopathic pulmonary fibrosis, though data on survival are now needed. However, trials with other non-steroid agents are currently

ongoing and new evidence may become available soon.

B A C K G R O U N D

Idiopathic pulmonary fibrosis (IPF) is a disease occurring primar-

ily in older adults, characterised by a chronic course and a gener-

ally poor prognosis (ATS 2000; ATS 2002). It is a specific form

of chronic fibrosing interstitial pneumonia limited to the lung,

associated with the pathological pattern of usual interstitial pneu-

monia (UIP) on surgical lung biopsy (Visscher 2006). The diag-

nosis of IPF also requires the exclusion of other forms of inter-

stitial pneumonia, including those associated with environmental

exposure, drugs or systemic disease (ATS 2000).

The aetiology of IPF is currently unknown, although a num-

ber of possible mechanisms involved in its pathogenesis have

been described. Among factors potentially associated with IPF

pathogenesis, cigarette smoking (Hubbard 1996; Iwai 1994; Steele

2005; Taskar 2006), environmental exposures (including metal

and wood dusts, Hubbard 1996; Hubbard 2000; Miyake 2005),

microbial agents (mostly Epstein-Barr virus (EBV), Kelly 2002;

Lok 2001; Stewart 1999; Tsukamoto 2000) and hepatitis C (Arase

2003; Meliconi 1996; Miyake 2005), and gastro-oesophageal re-

flux (Raghu 2006a; Tobin 1998) are those most studied. Genetic

factors have also been associated with susceptibility to develop IPF,

in both familial (Lee 2005; Rosas 2007; Steele 2005) and sporadic

forms (Checa 2008; Falfan-Valencia 2005; Zuo 2002).

The underlying process in IPF is thought to be fibroproliferative in

nature: it seems likely that the pathogenic process involves repeated

episodes of acute lung injury caused by a yet unidentified stimulus

(Du Bois 2010; Meltzer 2008).



The incidence of IPF has not been evaluated in large studies, but

available data estimate IPF incidence at 10.7 cases per 100,000

per year for men and 7.4 cases per 100,000 per year for women

(Coultas 1994). Moreover, some data indicate the incidence rate of

IPF to be increasing in recent years (Gribbin 2006). A recent study

from the US calculated an incidence between 6.8 and 16.3 per

100,000 people (Raghu 2006b). Prevalence estimates ranged from

2 to 29 cases per 100,000 (Iwai 1994; Karakatsani 2009; Scott

1990). Recent data provided a prevalence estimate between 14.0

and 42.7 per 100,000 persons depending on the diagnostic criteria

applied (Raghu 2006b). Comparing incidence and prevalence data

gives an estimate of survival with IPF of just two to three years.

IPF follows a variable clinical course in which periods of relative

stability are mixed with episodes of accelerated decline, possibly

resulting in respiratory failure and death (King 2005; Martinez

2005): this makes the natural history of the disease unpredictable

in the individual patient (Du Bois 2010; Meltzer 2008). IPF has

been reported as the primary cause of death in 89% of patients

who died in a cohort of 168 IPF patients in the placebo group of

a large randomised trial (Martinez 2005).

Episodes of acute respiratory worsening occur in a minority (5%

to 10%) of IPF patients (Azuma 2005; BUILD 1; Collard 2007).

When a cause cannot be identified for the acute respiratory de-

cline, the term acute exacerbation of IPF is used (Azuma 2005;

Churg 2007; Kim 2006; Kondoh 1993; Kondoh 2005; Kubo

2005; Martinez 2005). Although it is still unclear whether acute

exacerbations represent an acceleration in the pathological pro-

cesses involved in IPF, these clinical events are important in the

natural history of the disease since mortality after an acute exac-

erbation exceeds 90% (Collard 2007).

The histological features of IPF/UIP characteristically include le-

sions of different age and location, showing some preference for

the peripheral subpleural parenchyma. In this context, the patho-

logic hallmark and the main diagnostic criterion on lung pathol-

ogy is the heterogeneous appearance at low magnification in which

areas of fibrosis with scarring and honeycomb change alternate

with areas of less affected or normal parenchyma (ATS 2000; ATS

2002). Within the fibrotic regions there may be areas of chronic

lung injury with scar formation and patches of acute injury with

proliferating fibroblasts and myofibroblasts occurring at sites of

recent alveolar damage. Inflammation is usually mild, while fi-

brotic zones are composed of dense collagen: foci of proliferating

fibroblasts and myofibroblasts (the fibroblast foci) are a consistent

finding and a key diagnostic element.

According to current guidelines (ATS 2000), the diagnosis of IPF is

based on (i) the exclusion of other causes of interstitial lung disease

(ILD), (ii) abnormal pulmonary function tests showing a restric-

tive pattern and/or decreased diffusion lung capacity (DLCO) and

(iii) a radiologic pattern on high resolution computed tomography

(HRCT) of the chest showing bibasilar reticular abnormalities,

honeycombing and minimal ’ground glass’ opacity (ATS 2000).

These features in association with a typical clinical presentation

are usually adequate for diagnostic purposes and biopsy is gen-

erally considered unnecessary in clinical practice (Hunninghake

2001). Approximately 30% of cases show atypical features clini-

cally or on HRCT chest scan (extensive ’ground glass’ opacity),

which are usually considered to be an indication for surgical lung

biopsy (SLB) (Chan-Yeung 1997; Raghu 1999a). Transbronchial

biopsy (TBB) specimens generally provide unreliable material for

diagnostic purposes in IPF and the other ’alphabet soup intersti-

tial pneumonitides’ (Hanson 1976; Shure 1987; Shure 1989). A

revision of the current diagnostic criteria is expected to be pub-

lished very soon and a major emphasis will be put on the role of

chest HRCT. The typical HRCT UIP pattern will be defined as

the presence of reticular opacities, often associated with traction

bronchiectasis (Johkoh 1999; Nishimura 1992) and honeycomb-

ing (Hansell 2008) in the absence of extensive ground glass opaci-

ties: the distribution of HRCT lesions in IPF is typically basal and

peripheral, though often patchy. The presence of a typical HRCT

pattern and the exclusion of other causes for interstitial lung dis-

ease will be the main factors for IPF diagnosis, therefore reducing

the role of pulmonary function and bronchoscopy.

Why it is important to do this review

Soon after the publication of the first version of this review (Davies

2003), a number of basic research studies on the pathogenesis of

pulmonary fibrosis led to translational studies exploring innovative

approaches to the treatment of IPF. A variety of biological factors

and complex pathways have been implicated in the pathogenesis

of lung fibrosis and in particular of IPF (Hardie 2009). Although

most of the pharmacologic agents used in IPF trials have proved

to be effective in animal models of lung fibrosis, unfortunately

currently available animal models of pulmonary fibrosis do not

seem to provide an exact copy of IPF pathogenesis and appear to

be of limited utility in predicting the results in clinical IPF trials

(Gauldie 2008; Moeller 2008).

Only studies investigating treatment in IPF/UIP have been in-

cluded in this systematic review. In contrast to the previous version

of this review, when many of the included studies were carried

out using less stringent diagnostic criteria for IPF, the new studies

included in the present review have been conducted on a more ho-

mogeneous population of patients, and more vigorous inclusion

criteria based on American Thoracic Society (ATS) guidelines.

Optimal treatment of IPF remains contentious and at the moment

there are no clear-cut recommendations on how to treat patients

affected by IPF. Although this might be regarded as bad news

for patients and physicians, nonetheless, major advances have oc-

curred since the compilation of the previous version of this sys-

tematic review. A Cochrane Review investigating the role of cor-

ticosteroids in IPF (UIP) has failed to find any evidence that cor-

ticosteroids are of proven benefit in treatment (Richeldi 2003).



As a consequence, treatment of IPF with corticosteroid alone or

corticosteroid in combination with azathioprine is no longer rec-

ommended: this is reflected also in the recent guidelines released

by the British Thoracic Society (BTS 2008). However, some con-

troversial findings have arisen from some large randomised trials

of potentially efficacious drugs in IPF and the scope of this sys-

tematic review is to provide a comprehensive assessment of the

potential benefits of these treatments. Given the rapidly increasing

number of trials suitable for inclusion in a systematic analysis, in

this review it has been possible for the first time to perform meta-

analyses.

Much discussion is currently ongoing about the appropriate end-

points and outcome measures in clinical trials of IPF. Given the

progressive nature of the disease, survival (or progression-free sur-

vival) should be regarded as the most appropriate endpoint for

assessing drug efficacy in clinical trials. However, trials adequately

powered for mortality outcomes require large cohorts of patients

- which is quite challenging for a relatively rare disease, unless

studies are conducted on a national/international basis - and ma-

ture follow up. A logical surrogate for mortality has been the use

of change in FVC, as more rapid decline in FVC is associated

with increased mortality (King 2005). However, this measure is

not yet unanimously accepted by regulatory agencies as an ade-

quate stand-alone endpoint. On the other hand, exercise physiol-

ogy measures, such as the 6MWT or oxygen desaturation during

6MWT are complicated and poorly reproducible. Composite in-

dices of lung function tests have been shown to be predictive of

outcome (Wells 2003), but as yet there are no published studies

of their use in randomised clinical trials. Combined pulmonary

function end points may be more robust - with the possible in-

corporation of biomarkers, when more convincing data on their

value in the prediction of outcome or the stratification of individ-

uals in treatment groups will be available - and could represent a

valid option to be considered for future trials. However, because

IPF is a disease that tends to progress chronically, and is unlikely

to improve substantially, disease stabilisation is probably the best

outcome that can be expected, with important implications for

the design of future clinical trials.

Only six years after the previous systematic search, nine new ran-

domised controlled trials have been completed and published in

full or reported at major international conferences. Although at

the moment of writing this review only pirfenidone has been ap-

proved for IPF, and only in Japan, the currently available data and

the rapidly growing number of ongoing and planned randomised

trials make it likely that new drugs will be available in the future.

O B J E C T I V E S

To assess the efficacy of non-steroid agents in the treatment of

IPF patients, either as sole agents or in addition to corticosteroid

therapy.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) were considered for inclu-

sion. Placebo and non-placebo controlled trials were eligible.

Types of participants

Patients with a diagnosis of IPF, according to current guidelines

(ATS 2000).

Types of interventions

Any recognised non-corticosteroid agent, administered either as a

sole agent or in combination with corticosteroids and/or immuno-

suppressors versus either placebo or corticosteroids with/without

immunosuppressors. Interventions involving corticosteroids alone

for the treatment of IPF are excluded from this review.

Types of outcome measures

Primary outcome measures

1. Overall survival (OS)

2. Progression-free survival (PFS)

Secondary outcome measure

1. Absolute or percent predicted change from baseline in lung

function measured as vital capacity (VC) or forced vital capacity

(FVC)

Search methods for identification of studies

We searched the Cochrane Airways Group (CAG) Register (30

March 2010), the Cochrane Central Register of Controlled Trials

(CENTRAL) (The Cochrane Library, Issue 1, 2010), Ovid MED-

LINE to March week 5, 2010, EMBASE to week 13, 2010 and

PubMed to April 2010, with additional handsearching, including

abstracts of international conferences.

We submitted the following electronic search strategy to be

adapted by the CAG Trial Search Co-ordinator:

Idiopathic pulmonary fibrosis /or/ pulmonary fibrosis /or/ idio-

pathic interstitial pneumonia /or/ nonspecific interstitial pneumo-

nia /or/ non-specific interstitial pneumonia /or/ usual interstitial

pneumonia /or/ desquamative interstitial pneumonia /or/ crypto-

genic fibrosing alveolitis /or/ interstitial pneumonia /or/ idiopathic



interstitial lung disease /or/ chronic interstitial pneumonia /AND/

therapy /or/ azathioprine /or/ colchicine /or/ cyclophosphamide /

or/ cyclosporin /or/ cytokines /or/ interferon /or/ methotrexate /

or/ penicillamine.

For specific search strategies used on each database, please see Table

1 for EMBASE terms, Table 2 for MEDLINE search terms, Table

3 for CENTRAL search terms and Table 4 for PubMed.

Table 1. EMBASE search strategy

EMBASE

1. exp INTERSTITIAL LUNG DISEASE/

2. (pulmonary adj3 fibros$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug

manufacturer name]

3. (Interstitial adj5 pneumonia$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug

manufacturer name]

4. (interstitial adj3 lung disease$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug

manufacturer name]

5. alveoliti$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

6. 1 or 2 or 3 or 4 or 5

7. exp AZATHIOPRINE DERIVATIVE/ or exp AZATHIOPRINE/

8. exp COLCHICINE DERIVATIVE/ or exp COLCHICINE/

9. exp CYCLOPHOSPHAMIDE DERIVATIVE/ or exp CYCLOPHOSPHAMIDE/

10. exp Cyclosporin/

11. exp CYTOKINE/

12. exp METHOTREXATE DERIVATIVE/ or exp METHOTREXATE/

13. exp PENICILLAMINE/ or exp PENICILLAMINE DERIVATIVE/

14. (Azathioprine$ or colchicine$ or cyclophosphamide$ or cyclosporin$ or cytokine$ or interferon$ or methotrexate$ or penicil-

lamine$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

15. exp INTERFERON/

16. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15

17. 6 and 16

Table 2. MEDLINE search strategy

MEDLINE

1. exp Lung Diseases, Interstitial/

2. (pulmonary adj3 fibros$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug

manufacturer name]

3. (Interstitial adj5 pneumonia$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug

manufacturer name]

4. alveoliti$.mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

5. (Interstitial adj5 lung disease$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug

manufacturer name]

6. 1 or 2 or 3 or 4 or 5

7. exp Azathioprine/

8. exp COLCHICINE/

9. exp CYCLOPHOSPHAMIDE/

10. exp CYCLOSPORINE/



Table 2. MEDLINE search strategy (Continued)

11. exp CYTOKINES/

12. exp INTERFERONS/

13. exp METHOTREXATE/

14. exp PENICILLAMINE/

15. (Azathioprine$ or colchicine$ or cyclophosphamide$ or cyclosporin$ or cytokine$ or interferon$ or methotrexate$ or penicil-

lamine$).mp. [mp=title, abstract, subject headings, drug trade name, original title, device manufacturer, drug manufacturer name]

16. 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15

17. 6 and 16

Table 3. CENTRAL search strategy

CENTRAL

#1 LUNG DISEASES INTERSTITIAL

#2 (pulmonary near fibros*)

#3 (interstitial near pneumonia*)

#4 alveoliti*

#5 (interstitial near (lung next disease))

#6 (#1 or #2 or #3 or #4 or #5)

#7 AZATHIOPRINE

#8 COLCHICINE

#9 CYCLOPHOSPHAMIDE

#10 CYCLOSPORINE

#11 RECEPTORS CYTOKINE

#12 METHOTREXATE

#13 PENICILLAMINE

#14 (azathioprin* or colchicin* or cyclophosphamide* or cyclosporin* or cytokin* or interferon* or methotrexate* or penicillamin*)

#15 (#7 or #8 or #9 or #10 or #11 or #12 or #13 OR #14)

#16 (#7 and #15)

Table 4. PubMed search strategy

PubMed

“Idiopathic Pulmonary Fibrosis”[All Fields] AND

(“pirfenidone”[Substance Name] OR “pirfenidone”[All Fields]) OR

“Idiopathic Pulmonary Fibrosis/drug therapy”[MAJR]

Additionally, we contacted authors and sponsors of unpublished

studies presented at international meetings and reported as con-

ference abstracts.

Data collection and analysis

Selection of studies

Two review authors independently considered the abstracts of ar-

ticles identified using the search strategy described above, and ar-

ticles that appeared to fulfil the inclusion criteria were retrieved in

full. In addition, we handsearched full-text versions of identified

review articles for further RCTs. We reviewed and categorised each

identified article into one of the following groups.



• Included: RCTs that met the described inclusion criteria.

• Excluded: non-RCTs or RCTs that failed to meet inclusion

criteria.

When there was doubt, a third review author assessed the article

and a consensus was reached. If doubt persisted, we contacted

authors for further information.

Assessment of risk of bias in included studies

We separately assessed the methodological quality of the trials

based on five components: patient randomisation (both generation

of the allocation sequence and allocation concealment), blinding,

completeness of follow up and whether a study was multicentre

(Juni 2001; Moher 1998; Schulz 1995). We used the following

definitions in the assessment of the methodological quality.

Generation of the allocation sequence

1. Adequate: if the allocation sequence was generated by a

computer or random number table. Drawing of lots, tossing of a

coin, shuffling of cards, or throwing die was considered as

adequate if a person who was not otherwise involved in the

recruitment of participants performed the procedure.

2. Unclear: if the trial was described as randomised but the

method used for the allocation sequence generation was not

described.

3. Inadequate: if a system involving dates, names or

admittance numbers was used for the allocation of patients.

These studies are known as quasi-randomised and were excluded

from the present review for efficacy data. Trials with alternating

allocation were also excluded.

Allocation concealment

1. Adequate: if the allocation of patients involved a central,

independent unit; on-site locked computer; identically appearing

numbered drug bottles or containers prepared by an independent

pharmacist or investigator; or sealed, opaque envelopes.

2. Unclear: if the trial was described as randomised but the

method used to conceal the allocation was not described.

3. Inadequate: if the allocation sequence was known to the

investigators who assigned participants, the envelopes were

unsealed or transparent, or if the study was quasi-randomised.

Blinding

1. Adequate: if the trial was described as double-blind and the

method of blinding involved identical placebo or active drugs.

Particularly:

◦ double-blind (method described and use of a

placebo(s) or dummy technique meant neither the participant

nor the care provider or assessor knew which treatment was

given);

◦ single-blind (participant or the care provider or

assessor were aware of the treatment given).

2. Unclear: if the trial was described as double-blind or single-

blind but the method of blinding was not described.

3. Inadequate: if the trial was open label (all parties aware of

treatment).

Follow up

1. Adequate: if the numbers and reasons for dropouts and

withdrawals in all intervention groups were described and if 90%

or more of the participants randomised were included in the

analysis; or if it was specified that there were no dropouts or

withdrawals.

2. Unclear: if the report gave the impression that there were

no dropouts or withdrawals but this was not specifically stated.

3. Inadequate: if less than 90% of participants randomised

into the trial were included in the analysis or the number or

reasons for dropouts and withdrawals were not described.

In addition each study was assessed for the reliability of the diag-

nosis of IPF using conventional pre-specified criteria (ATS 2000).

Data synthesis

The measure of association chosen for combining the overall sur-

vival and progression-free survival was the hazard ratio (HR), es-

timated by dividing the hazard of mortality or progression in the

treatment group by the hazard in the control one. Values less than

one indicate that the experimental treatment is better than control,

values equal to one indicate that the two treatments have similar

efficacy, whereas values greater than one suggest that control is

better than treatment. The HRs estimated were directly extracted

from the original papers or provided by the authors or indirectly

obtained by using Parmar’s method (Parmar 1998).

In those studies comparing more than one dose and therefore with

more than two arms the comparison used for the meta-analysis

was conducted by selecting the arm in which the higher dose was

administrated and comparing it with the control one.

For FVC or VC the measure of association was the mean differ-

ences (in litres).

Study results were combined using the random-effects model. The

magnitude of heterogeneity was measured through the I2 statistic

(Higgins 2008).

R E S U L T S

Description of studies



See: Characteristics of included studies; Characteristics of excluded

studies; Characteristics of ongoing studies.

See: Characteristics of included studies, Characteristics of excluded

studies.

Results of the search

Two review authors assessed the abstracts that were returned from

the updated search. Fifteen studies (published since the previous

version of this review) were selected for full-text evaluation: of

these, based on the assessment of two review authors, nine new

RCTs were considered eligible for inclusion in the systematic re-

view. A total of six new trials were excluded on methodological

and other grounds.

Two additional studies were retrieved by contacting the commer-

cial sponsor and were considered eligible for inclusion.

Included studies

There were 15 eligible trials conducted in 3033 patients.

Three RCTs investigating the effects of interferon gamma-1beta

have been included; two of them (INSPIRE; Raghu 2004), en-

rolling 1156 patients, compared the treatment arm versus placebo,

while the third (Ziesche 1999) compared the combination of oral

prednisolone and interferon gamma-1beta (given subcutaneously)

versus oral prednisolone alone.

Two published trials assessing the efficacy of pirfenidone versus

placebo were eligible for inclusion (Azuma 2005; Taniguchi 2010).

In addition, after presentation of data on two large RCTs on ef-

ficacy and safety of pirfenidone at the International Conference

of the American Thoracic Society in 2009 (Du Bois 2009; Noble

2009), we contacted the sponsor (InterMune Inc., Brisbane CA,

USA) of these two RCTs on 22 May 2009. Data were received from

the sponsor on 29 September 2009, including study protocols, de-

mographics and baseline characteristics. In March 2010 the Spon-

sor’s Briefing Document for FDA Pulmonary-Allergy Drugs Advi-

sory Committee Meeting was made available for public disclosure

(Sponsor’s Briefing Document 2010). As such, four RCTs, involv-

ing overall 1155 patients and assessing pirfenidone versus placebo

were finally included (Azuma 2005; CAPACITY 1; CAPACITY

2; Taniguchi 2010). Two of them evaluated high and low-dose

pirfenidone versus placebo in a three-arm comparison study de-

sign (CAPACITY 2; Taniguchi 2010).

Three studies evaluated three different treatments compared to

placebo in patients with IPF: etanercept (Raghu 2008), ima-

tinib (Daniels 2010) and bosentan (BUILD 1). Two studies used

colchicine (Douglas 1998) or prednisolone plus anticoagulant

therapy (Kubo 2005) in the experimental group while using pred-

nisone or prednisolone alone in the control group, respectively.

A single RCT assessed the efficacy of azathioprine versus placebo

in IPF patients, while equal doses of prednisone were given in

both arms (Raghu 1991). The IFIGENIA trial evaluated the ef-

fectiveness of N-acetylcysteine added to ’standard’ therapy with

prednisone plus azathioprine compared to ’standard’ therapy plus

placebo (IFIGENIA). Finally, a randomised controlled study com-

pared prednisolone alone with a combination of cyclophospha-

mide and low-dose prednisolone (Johnson 1989).

Overall survival was an outcome evaluated in eight trials, but only

two of them (INSPIRE; Raghu 2004) were included in the meta-

analysis of the efficacy of interferon gamma-1beta. Ten trials in-

cluded progression-free survival, whereas the change of FVC or

VC was evaluated in 12 trials.

Excluded studies

Fifty-nine studies did not meet the inclusion criteria and therefore

were excluded from analysis. For full details of trial findings please

see Table 5.

Table 5. Details of excluded studies

Meier-Sydow 1970 was a retrospective case series of 6 patients with IPF treated with a variety of immunosuppressive agents including

oral corticosteroids, 6-mercaptopurine, cyclophosphamide and azathioprine. Details of the diagnostic methods used were not provided.

Most patients progressed clinically and/or by changes in PFTs and CXR.

Reasons for exclusion: The study failed to meet the inclusion criteria due to its uncontrolled, retrospective nature and lack of detail.

The original article was published in German.

Brown 1971. A retrospective case series of 5 patients with pulmonary fibrosis of uncertain aetiology and varied histological pattern, who

had either failed treatment with, were on large doses of or were unsuitable for oral corticosteroids. They were treated with azathioprine

at a dose of either 2 or 3 mg/kg/day. Chlorambucil was substituted for azathioprine in one subject due to thrombocytopenia and

cyclophosphamide in another due to side effects. Three subjects improved with immunosuppressive therapy.

Reasons for exclusion: The study failed to meet the inclusion criteria. It was an uncontrolled retrospective case series with patients

with a range of different diseases.



Table 5. Details of excluded studies (Continued)

Gross 1973 was a case series of 3 patients with a miscellany of conditions treated with D-penicillamine with reported improvement

by 6 to 8 weeks. Only one patient had IPF.

Reasons for exclusion: The study failed to meet the inclusion criteria. It was a small uncontrolled retrospective case series with only

one case of IPF included. The original article was published in German, with an English language abstract.

Schlehe 1973 was a retrospective case series of 6 patients with diffuse idiopathic pulmonary fibrosis treated with oral corticosteroids

and azathioprine. Many of the patients did not appear to have IPF as defined by modern criteria, with a desquamative cellular pattern

seen on histology obtained by OLB.

Reasons for exclusion: The study failed to meet the inclusion criteria, being a retrospective, uncontrolled, non-randomised case series.

In addition the subjects may have been suffering from another form of pulmonary fibrosis. The original article was in German, with

an English language abstract

Cegla 1974 was a retrospective open-label non-randomised case series examining the effects of D-penicillamine in high dose (3.6 g/

day) in patients with “severe” pulmonary fibrosis. Three out of six patients showed improvement in exertional dyspnoea and PFTs

after 2 months.

Reasons for exclusion: The trial was an open-label, non-randomised retrospective case series of only 2 months duration. As such it

failed to meet the inclusion criteria and was excluded. The original article was in German with an English language abstract.

Cegla 1975 compared 3 different regimens in the treatment of IPF: prednisolone 40 mg/day tapering to 0.5 mg/kg over 8 to 12 weeks

with either azathioprine 3 mg/kg, reducing to 2 mg/kg after 8 to 12 weeks (18 patients); D-penicillamine up to 3.6 g/day, reducing

after 12 months (7 patients) or K-para-aminobenzoate 3.0 g 4 times daily (5 patients). The trial was an open-label, unblinded and

non-randomised pilot study. Only patients with IPF/UIP were included using then current definitions, with diagnosis confirmed by

OLB or autopsy specimens in 14/27.

Azathioprine appeared to produce the greatest improvement in pulmonary function (VC) and D-penicillamine the greatest im-

provement in gas exchange (PaO2). Insufficient patients were treated with K-para-aminobenzoate to allow for any assessment of the

effectiveness of this agent.

It is possible that patients with forms of pulmonary fibrosis other than IPF were included as CT was not available as an investigational

tool at the time of this study.

Reasons for exclusion: The study failed to meet the inclusion criteria. It was open-label, unblinded and non-randomised.

Meier-Sydow 1975 was a retrospective case series of 8 patients with IPF or sarcoidosis treated with prednisolone and an additional

agent in 5 cases, either azathioprine (3 patients) or D-penicillamine (2 patients). Several patients appeared to deteriorate during the

up to 3 years of follow up provided but stabilisation of PFTs was observed in others. No distinction between patients with IPF or

sarcoidosis appears to have been made.

Reasons for exclusion: The study failed to meet the inclusion criteria. It was retrospective, open-label, unblinded and non-randomised.

Patients with sarcoidosis were included in the study. The original article was published in German.

Weese 1975 reported on a series of 3 patients with worsening pulmonary fibrosis despite corticosteroid therapy, with disease confined

to the lung in 2. Probably only 1 had IPF/UIP by modern criteria. The 2 patients with disease confined to the lung appeared to

stabilise following the addition of azathioprine whilst the third responded to cyclophosphamide.

Reasons for exclusion: The study failed to meet the inclusion criteria. It was a case series only with no randomisation or blinding

incorporated.

Cegla 1977 reviewed lung function data from 3 different therapies for IPF in a total of 32 patients in an open-label, non-randomised

uncontrolled trial. Prednisolone alone had no effect (4 patients), prednisolone and azathioprine improved VC by greater than 15%

in 50% of cases (20 patients), and resting PaO2 in 33%. Treatment with D-penicillamine and prednisolone (8 patients) improved

VC, resting and exercise PaO2 and was felt to be a superior therapy. A further pilot study combining prednisolone, azathioprine and

D-penicillamine was also described in 4 patients.




Reasons for exclusion: The study failed to meet the inclusion criteria, being a non-randomised, unblinded and uncontrolled trial

using a variety of interventions. The published article was in German, with an English language abstract provided.

Cegla 1978 was a retrospective review of therapy in IPF and presented data from a number of case series. Clinical details of some of

these patients had been included in other case series from the same author. The therapies used were prednisolone and azathioprine,

prednisolone and D-penicillamine and prednisolone, D-penicillamine and either cyclophosphamide or azathioprine. There was no

scientific comparison between groups.

Reasons for exclusion: The study was a retrospective review of a number of case series using differing combinations of immunosup-

pressive agents and as such it failed to meet the inclusion criteria. The original article was in German.

Fulmer 1978 was only ever reported in abstract form. This study examined the effects of the addition of azathioprine to prednisone

in a randomised, double-blinded, placebo-controlled fashion. Twenty-six patients in the “mid-course” of IPF were enrolled. One

group received prednisone at 1 mg/kg/day for 6 weeks, tapering to 0.25 mg/kg/day plus placebo: the other received prednisone in

a similar schedule plus azathioprine at 2.5 mg/kg/day. The diagnostic, inclusion and exclusion criteria used were not described, nor

were randomisation or blinding techniques described.

Follow up was at 6 and 12 months with review of “24 parameters derived from measurements of [PFTs and arterial blood gases]”.

Five patients developed drug toxicity, 2 in the placebo group and 3 in the azathioprine group. There were no significant differences

reported in any measured or derived parameter at the end of 6 or 12 months. Patients were also ranked by the degree of cellularity

and the severity of fibrosis seen in biopsy specimens, which however failed to unmask any significant differences. Some individual

responses were seen but these were not significantly different between groups. The authors concluded that there was no difference in

outcomes and considered that azathioprine was of no benefit.

Reasons for exclusion: This study was excluded as there was inadequate data provided in the published abstract. After 24 years it is

considered unlikely that additional meaningful information is available for this trial.

Goodman 1978. A pilot open-label, uncontrolled study of D-penicillamine therapy in 18 subjects aged between 21 and 64 years of

age who had failed treatment with steroids and/or immunosuppressive agents. Only 6/18 had pulmonary fibrosis without associated

collagen vascular disease, carcinoma, hiatus hernia, eosinophilic granuloma or extrinsic allergic alveolitis. 11/18 were female. Length

of survival ranged from 10 to 156 months with 50% survival after 48 months. 4/18 had adverse reactions requiring discontinuation

of therapy.

Reasons for exclusion: This trial was excluded as it was an uncontrolled, non-randomised pilot study with little published detail and

a heterogeneous study population. It was only published as an abstract.

Meuret 1978 was a case study of a 19 year old male with “an early stage of idiopathic pulmonary fibrosis” on biopsy, successfully treated

with prednisone, cyclophosphamide and vincristine. It was excluded from further analysis. The histological description provided was

not suggestive of IPF by modern criteria.

Reasons for exclusion: Case report only.

Schulz 1978 was a small retrospective series (3 patients) of cases of pulmonary fibrosis treated with D-penicillamine.

Reasons for exclusion: Case series only. The article was in German, with a brief abstract in English.

Winterbauer 1978. A prospective open-label uncontrolled trial that followed 20 patients with biopsy proven diffuse interstitial

pneumonitis. The histological appearance varied, and UIP, DIP and LIP were all observed in tissue specimens. All subjects were

treated with high-dose oral prednisone initially, tapering down to a maintenance dose of 10 to 20 mg daily after 7 weeks. All patients

were commenced on azathioprine (3 mg/kg/day as single daily dose) after 3 months of corticosteroid therapy. Treatment was for a total

of 12 months (9 months on azathioprine), following which it was discontinued in most patients. Azathioprine use was terminated

early in 3 subjects due to adverse reactions.

5/20 subjects had evidence of multisystem disease despite the exclusion of patients with known collagen vascular diseases. Additionally

2 subjects had recently developed malignant lymphomas. There was also a history of chronic nitrofurantoin use in 2 other subjects.

5/20 also showed precipitating antibodies to allergic alveolitis antigens.




12/20 improved vital capacity by greater than 20%. Two out of this group of 12 died during a mean 30-month follow-up period (range

15 to 44 months). The deaths were from 1) recurrent lymphoma and 2) superimposed infections (TB and pulmonary aspergillosis).

7/8 of patients in the unimproved group died during a mean 13 month follow-up period, 6 from respiratory failure. The difference

in death rates was highly significant (P = 0.0032).

In the 16 who survived 12 months or longer, there were statistically significant improvements in FVC, resting and exercise PaO2, P

(A-a)O2 and anatomical shunt. Amongst clinical features, only duration of symptoms and extrapulmonary manifestations of disease

correlated with therapeutic response, with most improvement in those with the briefest illness. Overall 60% improved with therapy. A

statistical assessment of the effects of azathioprine was not performed due to the small sample size. Histological variation in appearance

was more common in the treatment-responsive group.

Reasons for exclusion: This study was excluded from statistical analysis as it was an uncontrolled, open-label trial. There were several

subjects included with conditions other than UIP/IPF - histological appearances as described by the authors make it highly likely

that a considerable number of patients would have DIP under modern classification schemes. Additionally a number of subjects with

extra-pulmonary manifestations of disease may well have had an unrecognised multisystem disease process.

Meier-Sydow 1979 reported upon the long-term follow up of a group of patients treated with azathioprine or penicillamine in a

non-randomised, unblinded, uncontrolled fashion. Only patients with histologically proven (14/21) or clinically typical UIP were

included in the reported results, although it is unclear whether this distinction was made prospectively or retrospectively.

Patients were treated with prednisone 0.6 mg/kg orally daily reducing over 12 weeks to 0.1 to 0.25 mg/kg and either (1) azathioprine

3 mg/kg orally daily for 12 weeks reducing then to 2 mg/kg, or (2) D-penicillamine 5 mg/kg orally daily increasing weekly to 30 mg/

kg/day; after 1 year this was reduced to 15 to 20 mg/kg/day. 21 patients were included, with one withdrawal from each arm due to

side or adverse effects.

Follow up was for up to 8 years in the azathioprine group, with 5/11 subjects surviving this long. Follow up was for a shorter duration

in the 10 members of the penicillamine group, with only one individual followed for more than 4 years, apparently due to the death

of the other subjects, although there is some confusion in the article as published. There was no statistically significant difference in

survival between groups after 4 years. VC and static compliance significantly improved in the azathioprine group after 2 years but

not in the penicillamine group. The improvement in static compliance did not persist at 4 years.

Reasons for exclusion: This study was an uncontrolled, non-randomised, unblinded prospective trial. It was excluded as it failed to

meet the methodological criteria.

Haslam 1980. This was an observational study of 51 subjects with a diagnosis of “CFA” made on clinical, radiological and physiological

findings. However 15/51 also had evidence of connective tissue disorders in other systems making it likely that they in fact had another

form of pulmonary fibrosis. Of the remaining 36, histological confirmation of the diagnosis was available in 30. 10/36 were already

receiving immunosuppressive therapy in the form of prednisone. One subject was also taking penicillamine. BAL was performed at

study commencement. The value of differential lavage cell counts as a predictor for maintained response to treatment was assessed.

Response to therapy with prednisone or other immunosuppressive and anti-inflammatory agents was monitored over 12 months

to determine initial (1 month) and maintained (12-month) response. Subjects not already on immunosuppressive therapy were

commenced upon prednisone. Fifteen subjects were treated with other immunosuppressive agents, either instead of or in addition to

prednisone. Eight of this latter group responded to therapy, 6 of whom responded to cyclophosphamide. The study suggested that

the lymphocyte proportion in BAL fluid was important in predicting response to prednisone. The study failed to provide any more

details of clinical, radiological or physiological outcomes, nor did it distinguish between patients with pulmonary fibrosis confined

to the lung and those with other features of connective tissue disease.

Reasons for exclusion: The trial was excluded as it was uncontrolled, it failed to provide adequate primary or secondary outcome

measures, or adequate detail, and patients with conditions other than IPF were included.

Rust 1980 was a prospective non-randomised uncontrolled study of 25 patients with IPF followed for periods of up to 4 years. Patients

were treated with prednisone and either D-penicillamine or azathioprine. IPF was confirmed in 20 patients by OLB. There were no

significant differences in baseline characteristics between groups.

Both groups showed a significant improvement in PaO2 over the course of the study (up to 4 years). There do not appear to have

been significant changes in PFTs over the course of the study in either group. Little statistical detail was provided. Mortality rates




were not provided. Two patients in the D-penicillamine group developed nephrotic syndrome.

This study appeared to show some improvement in some parameters of lung function and stability in others but its uncontrolled

design, lack of statistical data make it difficult to draw meaningful conclusions from this study. The apparent lack of mortality is

unusual.

Reasons for exclusion: As a non-randomised open-label, uncontrolled study this trial failed to meet the inclusion criteria.

Costabel 1981 reviewed the effects of 3 different treatment regimens upon 15 patients with IPF. 12/15 underwent lung biopsy, 8 by

OLB and 4 by TBB with UIP being present in all specimens. Patients were “usually” started on a combination of 3 drugs: prednisolone

at 40 to 50 mg/day, tapering to 10 to 20 mg/day over 4 to 8 weeks; D-penicillamine at 300 mg/day, increasing by 300 mg weekly to

a maximum dosage of 3.6 g/day for 6 months, then 1.8 g/day for 6 months; and azathioprine or cyclophosphamide at 2 to 3 mg/

kg/day. Outcome was assessed in terms of improvement in VC and PaO2. Many required cessation of D-penicillamine due to side

effects, but this was not recorded in a systematic fashion. There was no randomisation or blinding procedure in the protocol and no

control group was incorporated into the study design.

6/15 were treated with prednisolone alone: one improved, “half of them” deteriorated and the rest remained stable. 4/15 were treated

with prednisolone and D-penicillamine, with 3 remaining stable and the other improving. The group treated with prednisolone and

azathioprine (6/15) showed improvement in 4/6 with only one worsening. Combined therapy with 3 drugs produced a significant

number of side effects. This seems to have been predominantly due to D-penicillamine and cyclophosphamide. Azathioprine seemed

to have been the best tolerated agent.

The authors concluded that the combination of azathioprine and prednisolone represented the best approach to therapy.

8/15 patients had serological evidence of a connective tissue disorder (Anti-nuclear antibodies [ANA], or rheumatoid factor [RhF]).

Good histological verification of the diagnosis was only available in 8/15 and therapy appears to have been introduced or discontinued

on an “ad hoc” basis. There was no statistical analysis of the results.

Reasons for exclusion: The study was an unblinded, non-randomised uncontrolled trial with only limited statistical analysis. In

addition half of the patients had serological evidence of a connective tissue disorder, casting doubt upon the diagnosis of IPF/UIP. It

failed to fulfil the criteria for inclusion and was excluded from further analysis.

Goodman 1981 reviewed 18 patients with interstitial lung disease and progressive fibrosis unresponsive to corticosteroids. Nine

suffered from collagen vascular syndromes. D-penicillamine was given in an open-label, uncontrolled, non-randomised trial. Patients

with collagen vascular diseases had improved survival (9/9 compared to 0/9 of those with“isolated”pulmonary disease). A historical

control group was also used as a comparator.

Reasons for exclusion: The study was uncontrolled, unblinded and non-randomised. Subjects had a variety of clinical diagnoses.

Rudd 1981 followed on from Haslam 1980. It was a prospective observational study investigating the presence of non-histological

features that might provide information regarding response to therapy and prognosis. One hundred and twenty subjects were included

in the study, of whom 26 had an associated systemic disorder. Histological confirmation was available in 74. 5/74 had evidence of

DIP and the rest were considered to have UIP.

Ninety-one patients were treated with immunosuppressive agents. 22/79 patients treated with corticosteroids responded to therapy

and 6/12 treated with other agents also responded. A high lymphocyte proportion in BAL fluid, more severely impaired initial FVC

and more recent onset of disease were associated with responsiveness to therapy. High lymphocyte proportions were also associated

with good prognosis. Increased eosinophil or neutrophil cell counts were associated with failure to respond. Increased BAL eosinophil

counts were associated with progressive deterioration. Response to treatment was associated with improved survival. In non-responders,

a more severe initial FVC was associated with shorter survival.

Reasons for exclusion: The study was excluded as it was an uncontrolled trial, included patients with other forms of pulmonary

fibrosis, only included a small proportion of patients treated with other immunosuppressive agents and failed to provide adequate

detail regarding outcomes.

Liebetrau 1982 was a retrospective case series of 58 patients treated with D-penicillamine (1.5 g/day) and prednisolone for pulmonary

fibrosis. Twenty-six improved in all parameters (VC, PaO2), 21 remained stable and 11 deteriorated on therapy.

Reasons for exclusion: The study was a retrospective case series and failed to meet the inclusion criteria. The article was in German,




with a published abstract in English.

Eliasson 1985. A retrospective case review of the use of cyclophosphamide in 8 patients from a group of 28 followed up in a university

respiratory clinic. Six patients had probable UIP and 2 DIP, the diagnosis being based upon histological specimens. All 8 had received

prednisone at an average maintenance dose of 26 +/- 13 mg/day (SD) at some point for an unknown length of time. The age at

presentation was 62 +/- 13 years, initial FVC 60 +/- 15% and initial DLCO 33 +/- 10%. No patients improved on cyclophosphamide

at a dose of either 50 or 100 mg/day. Seven of the 8 patients deteriorated whilst on this therapy. In addition, 6/8 suffered serious

adverse effects attributable to cyclophosphamide, necessitating discontinuation of the drug. The 2 patients receiving the highest

cumulative doses of cyclophosphamide both developed neoplastic illness. One patient possibly developed cyclophosphamide-induced

pulmonary fibrosis. The authors found no evidence that cyclophosphamide was effective in the treatment of pulmonary fibrosis.

Reasons for exclusion: The study was excluded as it was an uncontrolled, retrospective review and included patients with DIP.

O’Donnell 1987. In this non-randomised, prospective open-label parallel trial, patients with IPF referred to the Pulmonary Branch

of NHLBI, Bethesda were enrolled into 4 study groups to receive one of 3 interventions; corticosteroids alone, cyclophosphamide

alone or both corticosteroids and cyclophosphamide. Allocation to groups depended upon the results of an initial BAL. The study

was designed to investigate the potential pharmacological modulation of the neutrophil component of the alveolitis seen in IPF. The

patients had been previously diagnosed with IPF by (unspecified) “previously defined criteria”. All were regarded as being in the “mid-

course” of their disease. Patients enrolled in each group had a similar duration of disease. No other clinical information was provided.

The 4 study groups were:

Group 1. Untreated patients with a neutrophil count greater than 10% of total BAL cells. Treated with prednisone 1 mg/kg/day for

4 weeks, then tapering by 5 mg every 10 days to a maintenance dose of 0.25 mg/kg/day for the remainder of the trial.

Group 2. Untreated patients with a neutrophil count of less than 10% of total cells. Treated with prednisone as in group 1.

Group 3. Untreated patients with a neutrophil count greater than 10% of total cells. Treated with cyclophosphamide 1.5 mg/kg/day.

Group 4. Patients with a greater than 10% neutrophil count despite prednisone therapy (0.25 mg/kg/day) for at least 3 months.

Treated with cyclophosphamide in similar doses to group 3 in addition to continuing prednisone.

Evaluation comprised repeat BAL at 3 and 6 months. Mean proportions of neutrophils at each stage were compared to baseline values.

Group 1 and 2 patients showed no significant change in BAL neutrophil proportions at 3 or 6 months. Group 3 patients showed

a significant decrease in neutrophil proportions from baseline at 3 months, a change that was sustained at 6 months. This fall was

also seen in Group 4 following the administration of cyclophosphamide. There were no significant complications associated with

cyclophosphamide use in groups 3 and 4. There was no significant change in lung function in any of the study groups.

The study showed a significant change in neutrophil proportions in BAL fluid in the 2 groups treated with cyclophosphamide. From

the limited data presented it would appear that this was not accompanied by any change in respiratory function or clinical status.

Reasons for exclusion: The study was excluded as it failed to provide data for any of the desired primary outcomes. It is possible that

subjects in the 4 study groups were not adequately matched as it is unclear as to why some patients were already on corticosteroid

therapy. The description of patients as being in “mid-course” suggests that the subjects in this study may have been less severely

affected by their disease at the time of enrolment than those in some other studies. There was no placebo or true control group

included for comparison.

Turner-Warwick 1987. A study that investigated serial BAL as a means of assessing clinical progress. 32 subjects were followed for

up to 7 years in a prospective observational uncontrolled study. Twenty-six subjects had IPF and the remaining 6 also suffered from

associated connective tissue disorders. Histological confirmation of the presence of “CFA” was obtained in 27/32. Six subjects were

on immunosuppressive therapy at study commencement and an additional 20 were started on treatment during the course of the

study, 15 subjects received prednisolone and 11 received cyclophosphamide. Of this latter group 5 had already failed to respond

to prednisolone and 6 were started on cyclophosphamide de novo. 16/32 were also involved in a prospective randomised trial of

high-dose prednisolone versus low-dose prednisolone and cyclophosphamide, subsequently described in Johnson 1989. The authors

concluded that initial BAL cell counts could predict response to treatment and that serial BAL may be of benefit in guiding dosage

adjustment in those showing a response to immunosuppressive treatment.

Reasons for exclusion: This trial was excluded as it was not a randomised controlled trial, patients were on a range of therapies and

suffered from a heterogeneous collection of diseases. Additionally some of the subjects were also included in a subsequently reported




trial (Johnson 1989), with results which might otherwise have been duplicated.

Alton 1989 reported on a prospective open-label trial of cyclosporin A in IPF. Ten subjects were enrolled, 7 of whom had previously

undergone OLB. All patients had previously received treatment in both arms of another therapeutic trial, (Johnson 1989) with high-

dose prednisolone (60 mg/day) and cyclophosphamide (100 to 120 mg/day). Some had also received D-penicillamine or azathioprine

and all had deteriorated while on such therapy. Cyclosporin was commenced at a dose of 5 mg/kg/day. The mean duration of symptoms

prior to commencement of cyclosporin was 3.9 years (range 1.5 to 9). Mean DLCO at commencement was 17% of predicted (no

SD given). It is unclear whether and at what point other immunosuppressive therapy was discontinued. A control group of 7 patients

matched for sex, age, duration of disease, lung function (mean DLCO 18%) and histology and who had been similarly treated with

high-dose prednisolone and cyclophosphamide was used for the purposes of comparison. It is unclear whether treatment in this

group was continued. “Baseline” values for PFTs were taken from tests performed 3 and 6 months prior to the commencement of

cyclosporin.

Subjects were followed with monthly dyspnoea assessment, CXR and lung function. A change greater than 15% in FEV1, FVC or

DLCO from the previous recording was considered to be significant. It is unclear whether standardised validated scoring scales were

used for assessment of dyspnoea or CXR changes.

Three subjects were excluded from analysis, 2 due to super-added bronchogenic carcinoma discovered at post-mortem, and one due

to drug intolerance. Six of the remaining 7 reported either an improvement or no change in dyspnoea after one month; 3 out of 7

showed a 15% improvement in PFTs at 1 month and CXRs showed no substantial change. These improvements were not sustained

and all patients subsequently progressively declined in all outcome measures. Mean survival for treated patients was 5 months and

2.5 months for the control group. This difference was not statistically significant. It is not clear whether the 3 patients otherwise

excluded from analysis were included in this outcome. Nine out of 10 subjects developed side effects from the cyclosporin. One

patient was temporarily withdrawn from the trial due to the development of renal impairment which resolved following the cessation

of cyclosporin. Although not explicitly stated it is assumed that the patient was then re-entered in the trial. Another subject stopped

treatment and withdrew from the trial after 7 days due to side effects (facial flushing).

The authors concluded that the initial response to cyclosporin was encouraging and that this was unlikely to be due to a placebo

effect. Survival time was doubled, a finding considered to be of potential significance for patients awaiting heart-lung transplantation

for IPF. The subjects were at a very late stage of the disease process and it was felt that any substantial improvement would be unlikely.

It was felt that therapy initiated earlier or in less severe disease may prove more effective.

Reasons for exclusion: Insufficient data was provided to enable statistical assessment. There is some concern that the trial was not

truly prospective as some baseline data appears to have been retrospectively collected. With regard to the survival analysis it is unclear

as to whether the 3 otherwise excluded subjects were included in this calculation (e.g. on an intention-to-treat basis).

Fukazawa 1990 was a case report of the successful use of cyclosporin A in an 11 year old girl with idiopathic pulmonary fibrosis.

Reasons for exclusion: The study was a case report only and there were atypical features to the presentation. It did not fulfil the

selection criteria.

Meier-Sydow 1990 was published in abstract form only. It reported upon a prospective open-label non-randomised trial in patients

with biopsy proven IPF comparing 2 regimens: prednisone 40 mg/day tapering to 10 to 20 mg/day with either azathioprine 3 mg/

kg/day (15 patients) or D-penicillamine 1800 mg/day (11 patients). Although not explicitly stated there also appears to have been a

control arm allocated to prednisone only (11 patients).

Kaplan-Meier survival curves were calculated and Gehan statistics were used for between-group comparisons. There were no significant

between-group differences for baseline statistics or survival. There was a higher rate of side effects with D-penicillamine. No advantage

was demonstrated for either azathioprine or D-penicillamine.

Reasons for exclusion: The study failed to meet the inclusion criteria as it was a non-randomised, non-blinded trial. Additionally

there was a lack of detailed information provided in the published abstract.

Moolman 1991. This study was a retrospective review of 10 patients with progressive symptomatic interstitial lung disease of unknown

aetiology who were treated with cyclosporin A. Five of the 10 had histological features consistent with IPF and the other five had an

atypical progressive restrictive lung disease which could not be classified precisely. Of those patients considered to have IPF, 1 also had




mixed connective disease. Four of this group were on prednisone and 1 was additionally on cyclophosphamide. The fifth patient was

untreated. Those on therapy were deteriorating despite treatment. The second group of patients had a histological pattern that was

not consistent with a diagnosis of IPF, being a cellular, predominantly lymphocytic infiltrative process with minimal fibrosis. They

are not described here in detail.

All subjects were treated with prednisone at 20 mg/day and cyclosporin A at 7 mg/kg/day for 8 to 10 weeks. Doses were then

gradually reduced to 10 mg/day of prednisone and 3 mg/kg/day of cyclosporin. The combined treatment continued for 6 to 47

months (median 22). Clinical progress was monitored monthly, with FBC, LFTs, electrolytes, urea, creatinine and PFTs. CXRs were

performed after 3 months and thereafter at 6-monthly intervals. Response was assessed by changes in symptomatology using New

York Heart Association (NYHA) criteria and by PFTs. A 10% change in pulmonary function was considered to be significant.

8/10 patients showed an improvement in symptoms or lung function, 3 of these were from the IPF group. Of the IPF group 2 died

from infection, possibly contributed to by immunosuppression, one failed to respond to any immunosuppressive agent and died

within a year, one relapsed after 11 months on combination treatment, then stabilised with the addition of azathioprine, and finally

1 developed severe and resistant hypertension necessitating the withdrawal of combination therapy after 17 months with subsequent

relapse of IPF.

It is unclear whether any of the observed responses seen were due to cyclosporin or prednisone, although 4/5 had previously deteriorated

whilst on prednisone. Toxic effects possibly due to cyclosporin were not infrequent in the study group.

Reasons for exclusion: The study was a non-randomised open-label retrospective review, as such it failed to meet the inclusion criteria.

Additionally only 4 subjects were included who could be reasonably considered to have IPF by current criteria.

Baughman 1992. A non-randomised, open-label study of efficacy of intravenous cyclophosphamide in 33 symptomatic patients with

IPF. The subjects had either worsening disease or contraindications to corticosteroids. All had clinical features and PFTs consistent

with IPF, 16/33 had HRCT scans, the results of which showed changes consistent with IPF; 2 had OLB and 1 a post-mortem biopsy

all confirming IPF.

The chosen intervention was intravenous cyclophosphamide given second-weekly at an initial dose of 500 mg, escalating if WBC

remained above 3000 per cubic millimetre to a maximum of 1000 to 1800 mg. Corticosteroid therapy was tapered as tolerated. If

pulmonary function remained stable over a 4-month period then cyclophosphamide was given every 3 weeks.

Subjects were treated for at least 6 months or until death. The 18-month probability of survival was greater than 50%. For those

surviving 6 months (24) there was a significant rise in VC from 1.6 +/- 0.61L (SD) to 1.8 +/- 0.52 L (P < 0.01) which persisted for

at least 8 months. There was an associated significant fall in average prednisone dose from 32 +/- 13.0 mg to 4 +/- 10.4 mg (P <

0.01) by 12 months. 14/17 patients had discontinued prednisone by 12 months. Only 3/10 continued to receive prednisone at 18

months. Cyclophosphamide was considered to be well-tolerated. One patient required hospitalisation due to possible drug toxicity.

Three patients withdrew after 12 months. Thirteen died while receiving cyclophosphamide, 9 within 6 months. There were 11 deaths

from respiratory failure, One from pulmonary malignancy and 1 from unrelated cardiac disease. “Early death” patients received

significantly higher prednisone doses than survivors (P < 0.05).

The study authors concluded that intermittent intravenous cyclophosphamide therapy was associated with improved pulmonary

function and reduced corticosteroid use in patients with IPF who survived 6 months after the institution of therapy. Cyclophosphamide

appeared to have little effect upon mortality in the first 6 months.

Reasons for exclusion: The study was excluded as it was uncontrolled, non-randomised and un-blinded and as such failed to meet

the inclusion criteria. Additionally there appeared to be no distinction made between patients enrolled due to worsening disease (and

therefore possibly already on prednisone) and those enrolled due to contraindications to corticosteroids; thus the study population

may have been heterogeneous.

Shishido 1992. A case report of successful treatment of a case of biopsy proven IPF with iv methyl prednisone, oral prednisolone and

azathioprine. Article in Japanese, English abstract provided.

Reasons for exclusion: case report only

Behr 1993. This was a non-randomised, uncontrolled prospective trial that investigated changes in fibroblast chemotactic response

to bronchoalveolar lavage fluid over 6 months in a mixed group of 40 patients with IPF (22) or systemic sclerosis (18). Twenty-five

subjects were treated with prednisolone and 12 received additional cyclophosphamide if continuing deterioration occurred (in VC,




DLCO or PaO2). Fifteen subjects who refused drug treatment were also followed up for the duration of the trial and acted as de-

facto controls. Additional healthy subjects were also studied at baseline. They do not appear to have been matched with cases for any

parameter. They had several significantly different characteristics at baseline (VC, TLC, DLCO, resting and exercising PaO2 levels).

Analysis was based upon the division of subjects into 2 groups with baseline “high” or “low” levels of chemoattractant activity in BAL

fluid. The subjects were further subdivided into “treatment” and “no treatment” arms. No distinction appears to have been made

between therapy with prednisolone alone or with prednisolone and cyclophosphamide, or between different diagnoses. The treated

“high chemoattractant” group showed a significant improvement in VC, TLC and DLCO whilst the untreated “high chemoattractant”

group showed significant falls in VC, TLC and exercise PaO2 levels. There were no significant changes between treatment and no

treatment groups for the “low chemoattractant” arm.

Reasons for exclusion: This trial was excluded as it was neither randomised nor controlled and as such failed to meet the inclusion

criteria. In addition results were not reported separately for different diagnoses and findings were not reported separately for different

therapies.

Dayton 1993. This prospective non-randomised uncontrolled observational study followed 12 patients with a diagnosis of IPF made

on clinical and histological (in 7/12) grounds who were considered to have failed therapy with prednisolone, based upon objective

and subjective assessments. 10/12 were taking prednisolone at the commencement of the study. Cyclophosphamide was administered

as a once-monthly intravenous pulse dose. Those subjects taking prednisolone at the start of the study continued on this agent.

7/12 subjects died during the study, 6 from lung disease and one of complications of cholecystitis. Measures of lung function and gas

exchange remained stable throughout the study in both survivors and non-survivors. There was a trend towards older age (63 versus

57 years) and to a longer duration of symptoms before cytotoxic therapy (64 versus 50 months) among non-survivors but neither

measure achieved statistical significance. The duration of cyclophosphamide therapy was significantly longer in survivors than in non-

survivors (16 versus 6 months, P = 0.01). It was concluded that earlier intervention with cyclophosphamide might be of benefit in

the treatment of IPF.

Reasons for exclusion: This study was uncontrolled and non-randomised and as such failed to meet the inclusion criteria.

Peters 1993. A retrospective review of patients with a diagnosis of IPF seen at the Mayo Clinic. A total of 35 patients treated

empirically with colchicine were identified and adequate information for review was available in 23. Subjects had no clinical evidence

of connective tissue disease or other possible causes for fibrosis. CXRs and PFTs were also reviewed for these patients. OLB specimens

were available in 9 and showed UIP. Another 8 had undergone TBB with results consistent with IPF. Six were diagnosed without

histological confirmation.

Eighteen had received previous corticosteroid therapy and 5 received colchicine as their first treatment. Azathioprine and cyclophos-

phamide had each also been used in 1 steroid-treated patient. PFT before and after colchicine therapy was commenced were used as

the basis for studying efficacy.

Overall results of treatment with colchicine were that 5/23 improved, 9/23 remained stable and 9/23 worsened. Three of the 5 that

improved only received colchicine therapy. The drug appeared to be well-tolerated.

Reasons for exclusion: This study was retrospective, uncontrolled and non-randomised and as such failed to meet the inclusion criteria.

Venuta 1993 examined the efficacy of cyclosporin in reducing high prednisone doses in patients with IPF under consideration for

lung transplantation. It was an open-label uncontrolled study. The investigators were able to reduce the dose of prednisone from >

50 mg/day to 15 to 20 mg/day in 7/10 potential lung transplant candidates, enabling them to enter the transplant programme.

Reasons for exclusion: This study was an uncontrolled, non-randomised open-label study. As such it failed to meet the inclusion

criteria. In addition it examined a different endpoint to those chosen for review, namely reduction in prednisone dose

Meyer 1994. This study investigated the potential benefits of therapy with N-acetylcysteine, an agent capable of stimulating synthesis

of the anti-oxidant substance glutathione and therefore potentially reducing the oxidative damage implicated in the pathogenesis

of pulmonary fibrosis (Cantin 1987; Cantin 1989; MacNee 1995). It was an uncontrolled open-label study of the effects of N-

acetylcysteine upon BAL concentrations of glutathione after 5 days of therapy.

Reasons for exclusion: The study was an uncontrolled open-label study and therefore failed to meet the inclusion criteria.




Schwartz 1994a. This was a long-term prospective observational study of 39 subjects with IPF. At recruitment 18 were receiving no

immunosuppressive therapy, 14 were on corticosteroids and 7 were on cyclophosphamide. Excess longitudinal declines in TLC were

significantly associated with severe dyspnoea and cyclophosphamide therapy. Excess longitudinal declines in DLCO were significantly

associated with moderate to severe dyspnoea, cyclophosphamide treatment, higher pack-years of cigarette smoking and higher BAL

eosinophil concentrations. The study concluded that degree of dyspnoea, treatment with cyclophosphamide and smoking status were

independently associated with prognosis.

Reasons for exclusion: The study was a non-randomised longitudinal observational study with no formalised intervention and failed

to meet the inclusion criteria.

Van Oortegem 1994. A retrospective study that attempted to analyse the determinants of response to immunosuppressive therapy

with either prednisone alone or with prednisone and cyclophosphamide in subjects with IPF. A group of 25 consecutive subjects with

histologically confirmed IPF were reviewed. All were treated with prednisone (1 mg/kg/day) after initial evaluation. Follow up was at

3-monthly intervals. Patients who failed to improve with prednisone at any 3-monthly review had cyclophosphamide added to their

treatment. (100 mg/day). Response to treatment was defined as at least 10% improvement in FVC and/or DLCO from baseline 12

and 24 months after the commencement of therapy.

12/25 were considered to be responders at 24 months, 6/12 responding to prednisone alone, the other 6 to a combination of prednisone

and cyclophosphamide, the cyclophosphamide being started after 6 or 9 months (mean 7+/- 1.4 months[SEM?]).

Of the 13 non-responders, 3 were commenced upon both prednisone and cyclophosphamide at the outset, 8 had cyclophosphamide

added and 2 remained on prednisone alone (although this violated the treatment protocol).

A short duration of disease (less than 12 months) was related to response to therapy. Assessment (> 10% increase in FVC) after

3 months treatment was predictive of sustained response. Cyclophosphamide appeared to be of benefit only in those who initially

responded to corticosteroids. Patients with an initial FVC of greater than 90% were subsequently excluded from the analysis. With

these excluded, responders appeared to have a lower initial FVC than non-responders.

The authors considered that (1) a short symptomatic period increased the likelihood of a response, (2) early assessment of changes in

FVC predicted likelihood of response to therapy and that (3) a short-lived early response to corticosteroids could be sustained by the

addition of cyclophosphamide.

Reasons for exclusion: The study was uncontrolled, open-label and retrospective in design. As such it failed to meet the inclusion

criteria.

Meyer 1995. Another study that examined the effects of intravenous N-acetylcysteine upon glutathione concentration in BAL fluid

in IPF and normal controls. N-acetylcysteine infusion elevated BAL fluid glutathione levels in IPF but not in normal subjects.

Reasons for exclusion: The study was a short-term (< 3 months) open-label, non-randomised, controlled trial

Ziesche 1996 was an open-label study of the effects of interferon gamma-1beta (100 µg or 200 µg sc) in combination with low-dose

prednisolone (10 mg/day) in IPF. Only published as an abstract, it suggested that interferon-gamma had an additional benefit.

Reasons for exclusion: This study was an open-label, non-randomised trial and as such failed to meet the inclusion criteria. It was the

pilot study for the later (1999) RCT by Ziesche et al.

Behr 1997. This was an uncontrolled, prospective trial of N-acetylcysteine in a mixed group of 20 subjects (10 IPF, 10 collagen

vascular diseases). All subjects had received at least 6 months of immunosuppressive therapy prior to commencement of the trial.

Thirteen subjects were taking prednisolone, one was additionally receiving cyclophosphamide and 2 others azathioprine. The other 7

subjects had ceased immunosuppressive therapy at least 3 months before commencing the trial due to a lack of clinical improvement.

N-acetylcysteine was added 3 times a day for 12 weeks. The authors demonstrated a significant improvement in indices of lung

function and in levels of glutathione in BAL fluid after 12 weeks (predominantly the reduced form GSH).

Reasons for exclusion: Results were not reported separately for different diagnoses and findings were not reported separately for

different therapies. The study was an open-label uncontrolled trial.




Douglas 1997. This retrospective case review assessed the results of therapy with colchicine and prednisone as single agents. Medical

records were reviewed to identify patients treated initially with either colchicine or prednisone. Patients were included if they had

appropriate clinical findings, CXRs, PFT results and either HRCT scans showing typical changes of UIP/IPF or OLB specimens with

changes of UIP. They were also required to have had at least 1 follow-up PFT within 2 years of diagnosis. They were excluded if there

was a lack of characteristic x-ray or histological findings, if UIP was due to a specific cause, if initial treatment was with combination

therapy, if additional drugs were added before a follow-up PFT was performed, if there was no follow-up PFT within 2 years or if

there was documented drug intolerance necessitating discontinuation of therapy before the first follow-up PFT.

The colchicine group comprised 22 patients who met all the inclusion and exclusion criteria (out of a total 98 treated with colchicine

at the Mayo Clinic), who were then compared with 22 patients from a group of 102 undergoing OLB at the Mayo Clinic between

1974 and 1985 and previously coded as having histological evidence of IPF. These 102 specimens were reviewed and reclassified

according to current guidelines. A total of 80 were excluded, 35 as review showed pathology other than UIP, 33 with inadequate

follow up, 5 with prior therapy, 4 with non-diagnostic specimens, 2 with clinical evidence of disease other than IPF and 1 due to dual

initial therapy. Two colchicine treated patients were also included in another study from the same institution (Peters 1993).

Comparisons were made between the colchicine treated group and their historical prednisone treated counterparts. Time to treatment

failure was defined as the interval in months between baseline PFTs and the first follow-up study to show a significant decline from

baseline, 15% for FVC and 20% for DLCO. Follow-up was considered to end without PFT failure when a second drug was added to

the regimen before documented PFT failure occurred. Patients remaining on monotherapy and without PFT failure were classified

as non-failures when follow up ended at the last PFT. Follow up for all cases ended at 2 years due to inadequate further data.

There were significant differences at baseline between the 2 groups for the numbers undergoing OLB and HRCT, reflecting changes

in clinical practice and available technology; and in year of baseline PFT, reflecting the historical nature of one group. There were no

significant differences in demographics or baseline PFTs between groups. There was no significant difference between colchicine and

prednisone groups for changes between baseline and first subsequent PFT. There was no significant difference in rate of change in

PFTs over the follow-up period between the 2 groups. Failure curves for either FVC or DLCO, FVC alone and DLCO alone showed

no significant difference between groups.

In a combined total of 25 patients (11 prednisone, 14 colchicine) there was no significant decline in pulmonary function. There

was no significant difference in duration of follow up. Sustained improvement was considered difficult to assess as patients whose

condition declined tended to drop-out. No statistical comparison was given. Frequency of complications was also felt difficult to

compare and again no statistical comparison was given.

The authors concluded that there was no statistically significant difference in the rate of decline of pulmonary function between

groups. A trend towards more rapid decline with prednisone was suggested by the failure curves. There were a number of acknowledged

problems with the study. Diagnosis was based on different criteria in the different historical epochs chosen. Only a small number

of patients in the clinic registry had adequate follow-up data to allow for inclusion, possibly producing bias, as was the method of

selection of patients.

Other, unrecognised criticisms of the study include the possibility that the disease itself has changed. Incidence is believed to be rising

(ATS 2000) and the nature of the disease itself may have altered (Hubbard 1998). Other demographic considerations not explored

in the published study include race, geographical location of patients and other environmental factors (air pollution, work exposure

and practices etc) and differing patterns of possible predisposing infections (Hepatitis C, Epstein-Barr virus etc (Egan 1997)) all of

which could affect the validity of the comparison. No non-treatment comparison was made in either period. It is not known whether

the results from either prednisone or colchicine differed significantly in any way from no therapy.

Reasons for exclusion: The trial was a retrospective open-label review and as such failed to meet the inclusion criteria.

Garcia 1998. This study examined the effects of cyclosporin A upon in vitro production of pro-inflammatory cytokines in BAL fluid

recovered from normal subjects and subjects with a variety of interstitial lung diseases including IPF.

Reasons for exclusion: This was an acute, open-label study with none of the predefined outcomes. As such it did not meet the criteria

for inclusion

Kolb 1998 investigated the effects of intravenous cyclophosphamide pulse therapy in the management of IPF. The study retrospectively

reviewed 18 patients with progressive IPF treated for 1 year with iv cyclophosphamide. Diagnosis was based upon clinical, x-ray and

TBB findings in 13, with OLB in the other 5. Patients who had previously failed therapy with oral prednisolone were given an initial




dose of 500 mg of cyclophosphamide iv, increased by 100 mg every 2 weeks to a maximum dose of 1000 to 1300 mg (15 mg/kg). This

dose was given monthly for 1 year along with uro-protective adjuvant therapy with mesna. They were also given oral prednisolone

0.5 mg/kg/day, tapering after 6 weeks. After one year treatment was changed to oral prednisolone alone.

One patient was withdrawn from the study due to recurrent pneumonia. At one year, 6/17 showed improvement, 5/17 were stable,

(all classified as “responders”) and 6/17 had deteriorated. There was no significant difference in PFTs between groups after 1 year.

Oral prednisolone dose was significantly reduced in all patients after one year, but dosage in the non-responder subgroup was

not significantly reduced. The therapeutic benefit appeared to last for at least 3 months after ceasing cyclophosphamide. Seven

patients died after starting cyclophosphamide therapy. Five died within 4 months of commencing pulse therapy although this was

attributed to rapid disease progression rather than the agent. One subject died from pneumonia to which cyclophosphamide-induced

immunosuppression may have contributed.

The authors claimed to have arrested the disease process in 11/17 patients with the use of intermittent intravenous cyclophosphamide

and oral prednisolone. Long-term cyclophosphamide-related toxicity was apparently minimal and the drug was well-tolerated.

Reasons for exclusion: The trial was an uncontrolled and non-randomised study and as such failed to meet the the inclusion criteria.

In addition the value of using TBB as a diagnostic tool was questionable (Shure 1987, Shure 1989) and the demographic status of

patients included in the trial appeared to be highly variable, with ages ranging from 36 to 75 years old and disease duration from 6

to 90 months, suggesting a heterogeneous study population.

Selman 1998 was a non-randomised, prospective, open-label trial of the long-term efficacy of the combination of colchicine and/or

D-penicillamine with prednisone in the treatment of IPF.

56 patients with clinical, x-ray and functional features of ILD and a biopsy proven diagnosis of IPF were enrolled between 1983 and

1990 from clinics at the National Institute of Respiratory Diseases, Mexico. None had previously been treated with immunosuppressive

agents.

Patients were allocated to one of 4 treatment groups.

Interventions were:

(1) prednisone alone (15 patients)

(2) colchicine and prednisone (19)

(3) D-penicillamine and prednisone (11)

(4) D-penicillamine, colchicine and prednisone (11)

Prednisone was commenced at 1 mg/kg/day for 1 month, followed by a taper biweekly to a maintenance dose of 15 mg/day. Colchicine

was given at a dose of 1.0 mg daily and D-penicillamine 600 mg daily. Follow up was for 5 years, initially at 1 and 3 months,

thereafter at 3-monthly intervals for 2 years and 6-monthly after that. Outcomes followed were changes in dyspnoea scores, PFT

results (TLC and VC), resting arterial blood gas analysis and survival. All ABG testing was performed at an altitude of 2240 m and a

mean barometric pressure of 583 mmHg. Appropriate methods of statistical analysis were used for continuous and categorical data.

No details of the reasons for or the methods of allocation of patients to particular groups were provided.

Group 4 contained a significantly younger population (46 +/- 11 years) than groups 1 (55 +/- 10 years) or 2 (55 +/- 15 years) (P <

0.05). There were no other significant differences between groups at baseline.

Five patients were lost to follow up, 13 died in the first 2 years and 29 were dead by the 5-year follow-up date. Comparison of survival

curves showed no significant differences between groups. Women displayed a higher rate of mortality than men (23/36 versus 6/20,

P < 0.02). Age did not appear to be a prognostic factor.

Results of PFTs at 2 years showed no significant difference either within or between any of the groups but there was a non-significant

trend to improvement in PFTs in several groups (all results +/- SD):

Group 1: FVC (%) 41 +/- 17 to 51 +/- 18, TLC (%) 63 +/- 12 to 64 +/- 20, PaO2 (mmHg) 45 +/- 7 to 45 +/- 8, PaCO2 (mmHg)

35 +/- 8 to 32 +/- 4


33 +/- 5 to 37 +/- 4


35 +/- 5 to 39 +/- 17


35 +/- 6 to 44 +/- 7




It is possible that the apparent improvement in PFTs after 2 years is due to a survivor effect, with the sicker patients (presumably with

poorer lung function) dying during those first 2 years (13/56). Prednisone related side effects were common (90%) and more severe

than those due to the other study medications which were well tolerated.

The authors concluded that neither colchicine or D-penicillamine contributed to a better clinical response than prednisone alone.

This may reflect the relatively advanced stage of IPF seen in the study population (FVC < 50%). There was a significant difference

in mean age between some of the groups at baseline, notably group 4. Those in this group were on all 3 study agents suggesting that

they may have been deliberately placed in that group on the basis of age, possibly in the hope of a better outcome. Whilst the authors

did not consider that this affected their study, other authors (Raghu 1991) have found that when adjusted for age, a Cox regression

model showed a significant survival advantage for azathioprine. It is possible that an age adjusted effect may have been present in this

trial.

Reasons for exclusion: The study was an open-label, non-randomised trial and as such failed to meet the inclusion criteria. No details

were given regarding the details of patient assignment for each group and the suspicion must be that allocation may have been on

the grounds of age or other factors. There are therefore concerns about the degree of generalisability or reproducibility of the study

outcomes

Undurraga 1998 was a case series from Chile. 17 patients with clinically diagnosed IPF were enrolled in an open-label, non-randomised,

uncontrolled study. All were given colchicine in doses of 0.5 to 1.0 mg/day, according to tolerance and followed for up to 40 months.

Follow up used the scoring system proposed by Watters et al (Watters 1986) along with changes in arterial oxygenation and FVC. 6/

17 were considered to show a positive response to colchicine which was well-tolerated.

Reasons for exclusion: The study was a case series and as such failed to meet the inclusion criteria. The study was published in Spanish,

with an English language abstract provided.

Raghu 1999b. This was a prospective, open-label phase II study of the antifibrotic agent pirfenidone. Pirfenidone is a pyridone

molecule shown to inhibit TGF-beta in vitro and which appears to be effective in experimental animal models of pulmonary fibrosis.

Patients with progressive deterioration despite therapy with prednisone with or without immunosuppressive agents or those unwilling

or unable to tolerate conventional therapy were considered for inclusion. Diagnosis was based upon the presence of typical clinical,

radiological and histological features on OLB of IPF. Patients over 65 with typical features were also included if a TBB specimen

excluded the presence of malignancy, vasculitis, granuloma or infection. Other causes for deterioration were excluded as were other

possible causes for pulmonary fibrosis.

Chosen study endpoints were OS and measurable change in lung function after 12 months of therapy. A significant change was

defined as a 10% change in FVC or TLC or a 20% change in DLCO.

Pirfenidone was introduced over a period of 15 days, gradually increasing to a dose of 40 mg/kg/day up to a maximum of 3600 mg in

divided doses. Study medication was continued as long as the subject remained in the trial. Immunosuppressive therapy was stopped

on day 1 and prednisone tapered off over 6 to 8 weeks. Patients were not allowed to take concurrent medications used in IPF (e.g.

colchicine). Follow up was weekly for 2 weeks, monthly for 3 months, then 3-monthly. Appropriate statistical techniques were used

in the evaluation of outcomes.

There were 54 subjects, 42 with IPF confirmed by OLB, 8 with clinical features and a compatible TBB and 4 on clinical and

radiological features alone. There was no control group. Fourty one were able to complete PFTs at 6 months and 31 at 12 months.

The rest had either died or were unable to complete such tests. One-year survival was 78% (95% CI 66% to 89%), 2-year survival

63% (95% CI 50% to 76%). Three patients underwent lung transplantation and were removed from further follow up.

38/46 patients on prednisone were able to cease therapy and the other 8 were all able to reduce their dose. All 32 patients on

immunosuppressive agents were able to discontinue these.

In those able to be tested at 6 (41/54) and 12 months (31/54) the mean FVC and TLC stabilised after study entry. There was

insufficient data to assess changes in DLCO accurately. Similarly, oxygen saturation remained stable during follow up. The apparent

stability may had been due to a survivor effect.

At 6 months 29 had stabilised or improved FVC and 12 had deteriorated, 17 had established or improved TLC and 7 had deteriorated,

6 had died before 6 months and PFTs were not available for the remainder. At 1 year 22 had stable or improved FVC and 9 had

deteriorated, 15 had stabilised or improved TLC and 8 had deteriorated, 20 had stable or improved DLCO and 7 had deteriorated.

Overall there was a total of 12 deaths and one lung transplantation. DLCO less than 30%, age greater than 65 and male sex were




associated with decreased survival.

Gastrointestinal side effects were common (64%) but only 2 patients had sufficiently severe symptoms to warrant discontinuation.

Photosensitive skin reactions were also common (24%) and four (8%) discontinued therapy for this reason. Fatigue was noted in

42% but was not sufficiently severe to warrant discontinuation in any patient.

The authors concluded that treatment arrested decline in most patients in the study and that the medication was generally well-

tolerated.

Reasons for exclusion: The study was uncontrolled, non-randomised and open-label. As such it failed to meet the inclusion criteria.

Douglas 2000 was a retrospective review of all patients with pulmonary fibrosis seen at the Mayo Clinic, Rochester, between 1994 and

1996. It followed on from previous studies that suggested a trend towards better outcome with colchicine when compared to high-

dose prednisone (Douglas 1997; Douglas 1998; Peters 1993). This study assessed survival as a function of the different treatment

programmes, on an intention-to-treat basis. All patients were considered to have IPF/UIP on clinical, radiological and/or histological

criteria.

A total of 1901 patients with pulmonary fibrosis were identified, 34% of whom were considered to have IPF/UIP (581 patients)

. Treatment commenced at initial assessment was: none in 157 (32.2%), prednisone alone in 54 (11.1%), colchicine alone in 167

(34.3%), colchicine and prednisone in 71 (14.6%) and other treatments in 38 (7.8%). Oxygen therapy was also recommended in

133 (27.7%). Two hundred and fifty of these patients had received no drug therapy prior to their first Mayo Clinic visit (51.3%), 202

(41.5%) had previously received prednisone, 70 (14.4%) colchicine, 30 (6.2%) cyclophosphamide, 9 (1.8%) azathioprine, 3 (0.6%)

hydroxychloroquine, one (0.2%) methotrexate and 3 (0.6%) received other unspecified agents. In 125 (25.3%) only prednisone had

been used and only colchicine in 24 (4.9%). Seventy-four (15.6%) had previously received oxygen therapy.

Median survival was 3.2 years from the index visit, or 3.8 years if the initial diagnosis was made at the first visit. Univariate analysis

showed survival was worse with increasing age, male sex, patient referral for interstitial lung disease, progressive disease as assessed

by symptoms, CXR or pulmonary function, lower values of VC, VA, DLCO or resting SaO2 and with previous treatment with

prednisone, cyclophosphamide, azathioprine or oxygen. Survival was worse for those commenced on prednisone alone or prednisone

and colchicine when compared to those in whom no therapy was advised.

Multivariate analysis also showed that older age, male sex, lower DLCO and VA, and evidence of disease progression on PFTs were

all associated with a worse prognosis. After adjusting for age, sex, DLCO, VA and disease progression by PFT, there was no evidence

to indicate that survival was associated with recommended pharmacological or oxygen therapy.

The authors concluded that there was no evidence that colchicine had any additional benefit over no therapy in the treatment of IPF/

UIP. They also found no evidence that maintenance therapy with prednisone produced any survival benefit. Colchicine appeared to

be better tolerated than high-dose prednisone.

Reasons for exclusion: This study had an uncontrolled, retrospective design. As such it failed to meet the inclusion criteria. In addition

it included patients enrolled in other trials as described above.

Zisman 2000. This was an uncontrolled prospective trial of cyclophosphamide in 19 patients with biopsy proven IPF/UIP who failed

to respond (16) or could not tolerate (3) high-dose steroid therapy for 3 months.

Patients had clinical and investigational features consistent with IPF. Patients were excluded if they were found to have a disease

other than IPF. Pulmonary function tests were performed at baseline and at 3 months after the commencement of steroids and after

6 months or at discontinuation of cyclophosphamide therapy. Clinical severity was assessed using a 0 (best) to 100 (worst) point

composite clinical radiographic and physiologic score (CRP score). HRCT were scored on a 0 to 5-point scale. All patients underwent

bronchoscopy with BAL and TBB before undergoing OLB.

All patients were commenced on prednisone 1 mg/kg/day for 3 months. Changes in CRP score at 3 months were used to assess

response. Responders, non-responders and stable individuals were identified. Non-responders, stable patients and those unable to

tolerate high-dose steroids were commenced upon cyclophosphamide 2 mg/kg/day for a 6-month trial of therapy. Prednisone was

tapered over 4 weeks. Changes in CRP score were used to assess response to cyclophosphamide. Nine patients were unable to complete

the exercise component of the CRP assessment and their progress was assessed by changes to TLC, FVC, DLCO or pulse oximetry.

Nineteen patients were enrolled in the study. All had UIP on OLB. Only one patient showed a significant improvement on the

CRP score after 6 months of therapy. Seven remained stable, and this stability persisted after cyclophosphamide was stopped. Eleven

patients were classified as non-responders to cyclophosphamide. After long-term follow up (4.2 +/- 0.4 years), 7 patients had died,




all cyclophosphamide non-responders. This group appeared to have more severe disease, as assessed by baseline CRP score, HRCT

and lung function findings. 68% (13) exhibited toxicity to cyclophosphamide, necessitating cessation in 9.

The authors concluded that cyclophosphamide therapy was of limited efficacy in patients with IPF who failed to respond to prednisone.

There was a high incidence of side effects, often necessitating discontinuation of therapy.

Reasons for exclusion: The trial was an uncontrolled, open-label, non-randomised study. As such it failed to meet the inclusion criteria.

The CRP score that was used in patient assessment does not appear to be in widespread use and its external validity is uncertain. It is

uncertain how generalisable the study findings are. The study population may have been heterogeneous.

Douglas 2001 was a retrospective clinical record review of 487 patients with IPF confirmed by OLB or HRCT between 1994 and

1996. Survival was assessed as a function of the intention-to-treat at the time of initial clinic visit. Univariate analysis showed that

survival was significantly worse for patients treated with prednisone than no therapy and for those receiving oxygen compared to no

oxygen.

On multivariate analysis, reduced survival was associated with male sex, increasing age, lower DLCO, lower alveolar volume and a

history of worsening pulmonary function. When these factors were also included in a multivariate analysis there was no significant

difference in patients treated with prednisone or colchicine when compared to no therapy. Similarly, there was no difference between

oxygen users and non-users in the multivariate model.

Reasons for exclusion: This was an open-label, uncontrolled retrospective study which meant that this trial failed to meet the inclusion

criteria. In addition it was only published in abstract form and lacked statistical detail.

Homolka 2001. This study was presented in abstract form only at the ATS meeting, May 2001. An open-label, non-randomised

trial of cyclosporine A in 9 patients with histologically confirmed advanced IPF deteriorating on prednisone 1 mg/kg/day and/or

cyclophosphamide 2 mg/kg/day. Objective improvement was assessed by improvements in FVC and DLCO. The follow-up period

was not stated but appears to have been for a number of years. There were no objective improvements but 5 patients stabilised

symptomatically. Of the other 4 patients, 2 died.

Reasons for exclusion: The study was an open-label, non-randomised trial. As such it failed to meet the inclusion criteria.

Xaubet 2001. This Spanish study prospectively examined the clinical course of untreated patients with IPF compared to those treated

in an open-label, non-randomised prospective clinical trial utilising a variety of therapeutic interventions. Forty-three previously

untreated patients with IPF were enrolled over 3 years. There were 31 men, the mean age was 66 years (SEM 1, range 47 to 88). Twelve

were current smokers, 6 ex-smokers of at least 5 years standing and 25 lifelong non-smokers. Dyspnoea was present in 38/43 with a

mean duration of symptoms of 12 months (SEM 2, range 1 to 36). All patients had IPF/UIP as defined by current clinical criteria

and 18/43 (42%) had the diagnosis confirmed by OLB. Patients undergoing OLB were significantly younger than the remainder of

the study population.

PFTs including TLC and DLCO were performed. Fifteen patients also underwent an exercise test to determine symptom-limited

exercise capacity. 42/43 patients underwent HRCT. This was scored for the extent of parenchymal abnormalities using predefined

criteria by 2 radiologists blinded to other patient data. These data was subjected to semi-quantitative analysis. BAL was also conducted

although the results were not presented in any detail. Progression was defined as an increase in dyspnoea and/or < 15% fall in FVC

and/or DLCO. Response to therapy was defined as improvement in dyspnoea and/or > 15% improvement in FVC and DLCO.

Follow up with PFTs and CXR was performed at 3-monthly intervals or with clinical evidence of disease progression.

Treatment was initiated at diagnosis if the patient indicated a marked increase in dyspnoea over 12 months. Initial treatment was

with oral corticosteroids (1 mg/kg/day for 1 month), tapering by 10 mg every 2 weeks to a maintenance dose of 20 mg every second

day. Azathioprine or cyclophosphamide were added in the presence of disease progression or steroid side effects.

Twenty-nine patients received treatment at diagnosis (Group I). Twenty-six were followed up for 24 +/- 4 months with 3 lost to

follow up. Serial PFTs were available for 19, the other 7 being too sick to perform repeated PFTs. Eleven patients were commenced

upon azathioprine (3 mg/kg/day) or cyclophosphamide (100 -150 mg/day) during the study at a mean time of 16 +/- 3 months. 13/

26 died during the study, at a mean of 11 +/- 4 months after diagnosis; 10 due to disease progression, infection in 2 and pulmonary

embolism in 1. Overall 9 progressed, 5 were stable and 5 improved.

Group II patients (14 subjects) received no immediate treatment. Follow up was of 13 patients for 23 +/- 3 months with 1 being

lost to follow up. 8/13 were commenced upon therapy during the course of the study either with corticosteroids alone (7 patients)




or corticosteroids and azathioprine (1 patient). All patients demonstrated a significant fall in FVC and/or DLCO before therapy was

initiated. Treatment was initiated at a mean of 12 +/- 3 months after diagnosis. The other 6 patients remained stable during a follow-

up period of 19 +/- 4 months (15% of all study patients). It is not known whether these 6 differed in any way from the other patients

in Group II although the authors report no difference in “clinical, radiographical and HRCT findings”. There were no deaths in

Group II.

There were significant differences between the 2 groups at diagnosis. Group I patients were significantly more dyspnoeic, had a lower

FVC and a greater extent of ground-glass opacity on HRCT than those in Group II. As these were the criteria for inclusion in Group

I this finding is not unexpected. Group I patients had more severe disease at the onset of the study, although there was no evidence

that the duration of symptomatic disease was any longer. There were no significant differences in duration of preceding symptomatic

disease or other clinical and investigational findings.

The authors appeared to identify a subgroup of patients with “stable” or non-progressive IPF. How these patients differed from those

who initially required no treatment but who later developed progressive disease is not known. The relatively short follow-up period

may explain the apparent stability and a longer duration of follow up may have changed this finding. It is also not known whether

any of the Group I patients would have remained stable without intervention.

Reasons for exclusion: The study was a non-randomised, open-label prospective trial with significant differences between the “control”

group (Group II) and the initial treatment arm. As such it failed to meet the inclusion criteria.

Kalra 2003. In this study the authors reviewed the clinical records, radiological features, and pulmonary function data of 21 patients

treated with interferon gamma-1beta (200 µg administered subcutaneously 3 times a week). Mean duration of treatment was 8.2

months. While one patient only showed symptomatic and functional improvement, 7 discontinued treatment because of a perceived

lack of benefit. Furthermore, 11 patients (52%) died after a mean of 6.4 months of treatment, and follow-up pulmonary function data

suggested continued worsening in all but one patient. Minor adverse effects - consisting of flu-like symptoms, fatigue and macular

rash - were reported by 6/21 patients (29%).

Reasons for exclusion: The study was retrospective.

Collard 2004. This study retrospectively assessed whether combined corticosteroid and cyclophosphamide therapy improves survival

in patients with IPF. One hundred and sixty-four patients (82 treated and 82 untreated) matched by age at diagnosis (within 5 years)

and baseline FVC % (within 5%) were included in the study. Treatment consisted of corticosteroids (initial starting dose 0.5 to 1.0

mg/kg/day of oral prednisone or its equivalent) with the addition of oral cyclophosphamide (2 mg/kg/day with a total dose < 200 mg/

day). Corticosteroids were tapered to lower doses after several weeks and continued for at least 6 months and commonly 12 months.

No survival difference was found between patients who were treated (median survival: 1431 days) or untreated (median survival:

1665 days; P = 0.58). The lack of treatment effect persisted when analysis was restricted to patients diagnosed by surgical biopsy (n

= 24) or with a FVC % ≥ 60 (n = 107).


Nadrous 2004. This study retrospectively evaluated whether treatment with angiotensin-converting enzyme inhibitors (ACEI) and 3-

hydroxy-3-methylglutaryl coenzyme-A reductase inhibitors (statins) improved survival of patients with IPF. The rationale of the study

was that ACEI and statins have been shown to have antifibrotic properties in experimental models both in vitro and in vivo. Of 478

consecutive patients with IPF seen at Mayo Clinic Rochester from 1994 through 1996, 52 (11%) received ACEI, 35 (7%) received

statins, and 5 (1%) received both. Patients were on ACEI or statins for cardiovascular indications and lipid-lowering purposes.

For subjects receiving ACEI, the median survival from the index visit was 2.2 years, compared to 2.9 years for subjects not receiving

ACEI (P = 0.088), while the median survival was 2.9 years irrespective of whether patients were receiving statins or not (P = 0.573).

No significant difference in survival was observed between patients receiving either ACEI or statins versus those receiving neither at

the index visit (2.5 years versus 3 years, respectively; P = 0.066).


Kondoh 2005. This study evaluated the efficacy of cyclophosphamide combined with low-dose prednisolone in patients with IPF (n

= 27) as compared with patients with idiopathic fibrosing nonspecific interstitial pneumonia (NSIP; n = 12). All patients were treated

for 4 weeks with intermittent iv high-dose methylprednisolone (1 g/day for 3 days at 1-week intervals), followed by combination




therapy for 1 year with cyclophosphamide (1 to 2 mg/day) plus low-dose prednisolone (20 mg on alternate days). After 1 year of

combination therapy, 4 of 27 patients (15%) with IPF showed functional improvement (≥ 10% increase in VC % predicted), 14

(52%) remained unchanged, and 9 (33%) had worsened - which did not significantly differed from pre-treatment baseline data (70.8

± 15.5% versus 72.1 ± 17.3%: P = 0.52). On the other hand, in the fibrosing NSIP group, 8 of 12 patients had improved, 4 remained

unchanged, and none had worsened (56.7 ± 12.7% versus 77.2 ± 16.1%; P = 0.001). Median survival of IPF patients was 4.1 years,

significantly worse than that of fibrosing NSIP patients (P = 0.002).

Adverse events attributable to cyclophosphamide - e.g. haemorrhagic cystitis, leukopenia, myelodysplastic syndrome, herpes zoster,

alopecia and aspergilloma - were reported by 8 patients, with 5 (13%) requiring discontinuation of treatment.

Reasons for exclusion: The study was retrospective and with only one arm.

Antoniou 2006. In a prospective multicentric open-label study, 50 patients were randomly assigned (2:1) to receive 200 µg interferon

gamma-1beta administered subcutaneously 3 times weekly plus 10 mg oral prednisolone daily (n = 32) or 1 mg/day oral colchicine

plus 10 mg oral prednisolone daily (n = 18) for 24 months. Patients were eligible if they had a FVC ≥ 55% and ≤ 90% of the

predicted value, a DLCO ≥ 35% predicted and a PaO2 > 7.3 kPa while breathing room air at rest.

This study had no pre-specified end-points. In the intention-to-treat population, 5/32 (16%) patients in the interferon gamma-1beta

arm and 7/18 (39%) in the colchicine arm died after a median follow-up period of 25 months (P = 0.028). The hazard ratio for death

in the interferon gamma-1beta group, compared with the colchicine group, was 0.30 (95% CI 0.07 to 0.86). In addition, 62% of

patients in the interferon gamma-1beta arm had improved or stable disease compared with 17% in the colchicine arm (P = 0.014)

after 24 months of therapy. Furthermore, the interferon gamma-1beta group exhibited a higher FVC % predicted at 24 months (P =

0.04). No significant differences were observed in resting arterial oxygen tension, TLC % predicted, DLCO % predicted and disease

progression by HRCT patterns between the 2 treatment groups. Constitutional symptoms, including fever, myalgia, rigors, headache

and flu-like syndrome, were significantly more common among patients who received interferon gamma-1beta (P = 0.01).

Reasons for exclusion: The study was open-label comparing 2 different non-steroid agents. As such it failed to meet the inclusion

criteria.

Pereira 2006. In this non-randomised, retrospective, open-label study, the authors compared the survival (primary outcome) of patients

with IPF treated with corticosteroids (CS) alone (group I; n = 26) to survival of patients treated with CS plus immunosuppressive

agents (group II; cyclophosphamide, n = 53 or azathioprine, n = 3). The secondary endpoint was change in FVC (% predicted). The

study population consisted of 82 IPF patients

The dose of prednisone or equivalent was at least 0.5 mg/kg/day for 3 consecutive months, followed by tapering to 10 mg given for

1 year or more, associated or not with immunosuppressive agents given for at least 6 months. The CS used were oral prednisone

(median dose = 30 mg), or weekly pulses of iv methylprednisolone (median dose = 1 g). The immunosuppressive agents used were

cyclophosphamide (1 to 2 mg/kg/day orally, median dose = 100 mg/day or iv monthly, median dose = 750 mg) or oral azathioprine

(2 to 3 mg/kg/day). Median time of treatment was 14 months for CS and 12 months for cyclophosphamide.

Median survival was 25 months for group I, and 45 months for group II (P = 0.01). In addition, FVC declined 251 ± 0.31 ml in

group I compared with 105 ± 230 ml in group II (P = 0.045).

Reasons for exclusion: The study was non-randomised retrospective study and open-label.

Roig 2010. This is a prospective, non-randomised study with parallel groups assessing the efficacy of prednisone plus pulsed intravenous

cyclophosphamide (n = 21) versus prednisone plus azathioprine (n = 25) in patients with IPF. Treatment duration was 24 months.

Prednisone was given at 0.5 mg/kg/day during the first month, 0.25 mg/kg/day for the 2 months, followed by 0.25 mg/kg/day on

alternate days for 9 months, then reduced to 10 mg/day on alternate days for 1 year. Cyclophosphamide was given at a dose of

750 mg/m2. Azathioprine was given at a dose of 2 mg/kg/day (maximum 150 mg/day). All patients also received N-acetylcysteine

(1800 mg/day) omeprazole (20 or 40 mg/day) and osteoporosis preventive treatment with calcium supplementation, vitamin D and

bisphosphonates. Primary outcomes were overall survival or progression-free survival until lung transplantation. Secondary outcomes

were changes in FVC, DLCO and PaO2 at 36 months. Overall survival or progression-free survival until lung transplantation was

76% in cyclophosphamide group versus 44% in the azathioprine group (P = 0.028). Differences in secondary outcomes were not

statistically significant between the 2 groups.

Reasons for exclusion: The study was a non-randomised unblinded prospective study.



ABG: arterial blood gases; BAL: bronchoalveolar lavage; CRP: C-reactive protein; CS: corticosteroid; CXR: chest x-Ray; DIP: desqua-

mative interstitial pneumonia; DLCO: diffusion lung capacity; FBC: full blood count; FEV1: forced expiratory volume in one

second; FVC: forced vital capacity; HRCT: high resolution computed tomography; ILD: interstitial lung disease; IPF: idiopathic

pulmonary fibrosis; iv: intravenous; m: metres; LFT: lung function test; LIP: lymphocytic interstitial pneumonia; OLB: open-

lung biopsy; OS: overall survival; PFT: pulmonary function tests; SaO2: arterial oxygen saturation; SD: standard deviation; TBB:

transbronchial biopsy; TLC: Total Lung Capacity; UIP: usual interstitial pneumonia; VC: vital capacity; WBC: white blood cells.

Risk of bias in included studies

The risk of bias is summarised in Figure 1 and full details can be

found in the Characteristics of included studies table.



Figure 1. Risk of bias summary: review authors’ judgements about each risk of bias item for each included

study.



Allocation

The amount of information available to determine the processes

for generating the randomisation sequences in the studies was lim-

ited. We have been able to verify that they were adequate in only

two studies (IFIGENIA; Kubo 2005). Concealment of the ran-

domisation sequences was adequate in four studies (CAPACITY

1; CAPACITY 2; Daniels 2010; INSPIRE). Since the majority

of these studies have been designed and conducted for regulatory

purposes, it is likely that the allocation procedures were adequate.

Blinding

Identical presentation of treatment and control therapies was con-

firmed in all but four studies which were open-label (Douglas

1998; Johnson 1989; Kubo 2005; Ziesche 1999).

Incomplete outcome data

We judged the follow up of study participants to be inadequate in

two of the studies included (IFIGENIA; Kubo 2005).

Effects of interventions

Among the 15 included studies, six trials were considered suit-

able for inclusion in meta-analyses, which have been performed

for two drugs, interferon gamma-1beta and pirfenidone (partly

using unpublished data). The results for each trial are described

below (grouped by treatment) and full details can be found in the

Characteristics of included studies table.

Efficacy of interferon gamma-1beta

Three trials assessing efficacy of interferon gamma-1beta were

identified (INSPIRE; Raghu 2004; Ziesche 1999). Two studies

(INSPIRE; Raghu 2004) provided the information about mortal-

ity by reporting the estimates of the hazard ratio (HR). The com-

bination of the two estimates did not show any statistically signifi-

cant differences in mortality between interferon and placebo (HR

0.88, 95% CI 0.47 to 1.64). The results do not provide evidence

that interferon is more effective than placebo (Figure 2). A single

study (Raghu 2004) observed that interferon gamma-1beta ther-

apy did not significantly affect progression-free survival (HR 0.9,

95% CI 0.6 to 1.2; Analysis 1.2). The two studies also did not

show a significant difference with respect to the change in FVC

(Raghu 2004: -0.20 litres in the interferon gamma-1beta group

versus -0.16 litres in the placebo group; INSPIRE: -15.3% versus

-14.5%; P = 0.691). The Ziesche 1999 study reported a signifi-

cant increase in FVC with interferon gamma-1beta; however, the

authors did not provide enough information to allow these results

to be included in a meta-analysis.

Figure 2. Forest plot of comparison: 1 Interferon gamma-1beta versus placebo, outcome: 1.1 Overall

survival.

Efficacy of pirfenidone

Four trials assessing efficacy of pirfenidone were identified (Azuma

2005; CAPACITY 1; CAPACITY 2; Taniguchi 2010). Azuma

2005 did not report data on progression-free survival. Therefore

three studies (CAPACITY 1; CAPACITY 2; Taniguchi 2010)

were included in the meta-analysis of progression-free survival:

CAPACITY 1 and CAPACITY 2 reported the estimate of the haz-

ard ratio as well as its 95% confidence interval; Taniguchi 2010

did not provide the value of the hazard ratio, which was instead

indirectly estimated by using the information reported by the au-

thors on the survival curves, such as percentage of progression-free

survival and number of patients at risk at different points in time,

and the P value of the log rank test. Similar and significant differ-

ences were observed in progression-free survival time between the

pirfenidone and the placebo arm for two studies (CAPACITY 2;



Taniguchi 2010), while a non-significant effect was observed for

CAPACITY 1.

The summary of the three estimates suggests that pirfenidone re-

duces the risk of progression by 30% (HR 0.70, 95% CI 0.56 to

0.88) (Figure 3).

Figure 3. Forest plot of comparison: 2 Pirfenidone versus placebo, outcome: 2.1 Progression-free survival.

Two studies included FVC as a primary endpoint (CAPACITY

1; CAPACITY 2) while two (Azuma 2005; Taniguchi 2010) used

VC. Only two studies (Azuma 2005; Taniguchi 2010) reported the

results in litres, whereas the other two (CAPACITY 1; CAPACITY

2) reported the results in percent of predicted FVC at different

points in time from baseline. Based on the unpublished data re-

ceived from the sponsor, the mean decline from baseline in percent

predicted FVC at week 72 did not differ between the pirfenidone

and placebo groups in CAPACITY 1, and in CAPACITY 2, the

higher dose group (pirfenidone 2403 mg/day) successfully met

the change from baseline in percent predicted FVC with a sig-

nificant reduction in the mean decline compared with placebo.

The authors of the latter two studies analysed the results by using

ANCOVA rank analysis. The heterogeneity of statistical methods

across studies did not allow us to combine their results. In Azuma

2005 and Taniguchi 2010 significant differences were observed in

terms of decline of VC between the pirfenidone and the placebo

groups. The result of meta-analysis, analysing 314 patients, con-

firms the beneficial effect of pirfenidone on the change of VC

compared to baseline (Analysis 2.2).

Efficacy of cyclophosphamide

A single study (Johnson 1989) compared prednisolone alone with

a combination of cyclophosphamide and low-dose prednisolone.

Time until failure of the first treatment regimen or time to death

was significantly longer for the patients allocated to the treatment

arm (P < 0.05) as well as survival, although this was not statistically

significant.

Efficacy of azathioprine

Azathioprine was utilised in one included trial (Raghu 1991). Sur-

vival was not significantly different between the two groups (P

= 0.16), but when the analysis was adjusted for age, there was a

significant difference favouring azathioprine (P = 0.02) at up to

nine years follow up (Analysis 3.1). There were no significant dif-

ferences in percent predicted change FVC from baseline between

study groups although trends to improvement with azathioprine

were observed (Analysis 3.2).

Efficacy of colchicine

Colchicine was studied in one trial (Douglas 1998). Kaplan-Meier

survival curves showed a trend towards increased survival in the

treatment arm, although this difference did not achieve statistical

significance (Analysis 4.1). After three months there was not a

significant difference between groups in percent predicted change

of FVC from baseline (Analysis 4.2).

Efficacy of N-acetylcysteine

In the IFIGENIA study (IFIGENIA) N-acetylcysteine slowed the

deterioration of VC at 12 months. The overall survival did not

differ between the arms (Analysis 5.1). The difference in the ab-

solute change of VC from baseline between the treatment and the

control arm failed to reach a conventional statistical significance

(Analysis 5.2). The authors reported also the absolute difference

of the LS-LOCF for VC (least squares mean from the last obser-

vation carried forward analysis of variance) between the treatment



and the control arm, which was 0.18 litre, 95% CI 0.03 to 0.32

(IFIGENIA).

Efficacy of anticoagulant therapy

A single RCT on anticoagulant therapy (Kubo 2005) showed a

significant difference in survival between the two study groups in

favour of the treatment arm, with HR 0.34, 95% CI 0.12 to 0.97

(Analysis 6.1). Furthermore, the mortality associated with acute

exacerbations of IPF was significantly reduced in the anticoagulant

group as compared to the non-anticoagulant group (18% versus

71%, respectively; P = 0.008).

Efficacy of etanercept

Etanercept, considered in a single RCT (Raghu 2008), did not

affect the reduction in disease progression as compared to placebo

(estimated HR 0.61, 95% CI 0.32 to 1.17) (Analysis 7.1) nor the

change in the percent of predicted FVC from baseline at 48 weeks

(mean decline of 0.1 percent ± 0.3 versus 0.2 ± 0.3, Analysis 7.2).

Efficacy of imatinib

A single RCT study using imatinib (Daniels 2010) failed to

demonstrate differences between the imatinib and the placebo

group with regard to combined measure of disease progression or

death (HR 1.05, 95% CI 0.56 to 1.96) (Analysis 8.1). During the

96-week trial there were eight deaths in the imatinib group and

10 deaths in the placebo group (log rank test P = 0.64, Analysis

8.2). Change in FVC was not affected by imatinib at 96 weeks (P

= 0.947) (Analysis 8.3). Thirty-five (29%) patients discontinued

the study without reaching the primary endpoint (imatinib, 32%;

placebo, 27%; P = 0.51).

Efficacy of bosentan

Bosentan was evaluated only in one study (BUILD 1): a positive

trend in favour of bosentan was observed in time to death or

disease progression (HR 0.61, 95% CI 0.33 to 1.14) (Analysis 9.1),

which was more pronounced in a rather arbitrarily chosen patient

subgroup diagnosed by surgical lung biopsy (post hoc analysis,

HR 0.31; P = 0.009).

D I S C U S S I O N

This systematic review represents a major update of the previous

version. There has been a substantial increase in both the number

and quality of randomised controlled trials on IPF treatment. In

the last version of this review, the quality of the retrieved stud-

ies was generally poor and only three trials (assessing three dif-

ferent treatments) of suitable quality for inclusion were identi-

fied. Six years later, the number of included studies has increased

to 15 (evaluating 10 drugs) and the methodological quality of

these new studies was judged overall to be high. As a direct con-

sequence, the findings of the review have changed substantially.

The retrieved data allowed the combination of the results of single

studies into two meta-analyses and improved the precision of the

estimates from the available studies; improving our knowledge of

IPF treatment. The willingness of two pharmaceutical companies

(Shionogi in Japan and Intermune in USA) to provide us with

unpublished data has permitted us to explore the evidence base

more thoroughly than would otherwise have been possible based

on the results reported in the current literature.

Two placebo randomised controlled trials (INSPIRE; Raghu

2004) assessing subcutaneous interferon gamma-1beta, both of

high quality and evaluating a total of 1156 IPF patients, did not

confirm the initial finding of a small RCT (Ziesche 1999) and

the results of a post hoc analysis on a sub-population of patients

with early disease from the first of these two large studies. A meta-

analysis of these two trials did not provide evidence of a beneficial

effect for interferon gamma-1beta in improving the overall sur-

vival of IPF patients (HR 0.88, 95% CI 0.47 to 1.64; P = 0.68).

Four placebo randomised controlled trials (Azuma 2005;

CAPACITY 1; CAPACITY 2; Taniguchi 2010) explored the effect

of pirfenidone on the decline of pulmonary function, as measured

by means of decrease in FVC or VC; three of them (CAPACITY 1;

CAPACITY 2; Taniguchi 2010) also assessed the effect on progres-

sion-free survival (as defined by the authors) which was obtained

for 894 IPF patients. The combination of the estimates of three

studies (CAPACITY 1; CAPACITY 2; Taniguchi 2010) showed

that pirfenidone significantly reduced the risk of disease progres-

sion by 30% (HR 0.70, 95% CI 0.56 to 0.88). Although all four

studies assessed the effect of pirfenidone on pulmonary function

(by measuring either FVC or VC), differences in reporting results

did not allow us to combine the data from all these studies. Whilst

our decision not to combine these data from different RCTs may

be justified on methodological grounds, they nevertheless assess

similar functional endpoints and there is a need for future IPF

trials to be rigorous and homogeneous in both their design and

reporting. We emphasise the importance of accurate description

of all methodological aspects to enable reliable appraisal and cor-

rect interpretation of results. Only the results on pulmonary func-

tion from two studies (Azuma 2005; Taniguchi 2010) could be

combined in a meta-analysis, involving 314 Japanese IPF patients:

a positive effect of pirfenidone in slowing the reduction of pul-

monary function was observed.

The findings of these meta-analyses on both progression-free sur-

vival (PFS) and lung function seem to indicate a clinically relevant

effect of pirfenidone in patients with IPF. However, despite a sig-

nificant effect on the combined endpoint of progression-free sur-

vival, some uncertainty applies to our findings, since the results of

two large RCTs included in the meta-analysis have not been pub-

lished yet in peer-reviewed journals (CAPACITY 1; CAPACITY



2). The recent approval of pirfenidone for IPF treatment in Japan

might suggest a potential relevance of the results of this drug in

IPF. On the other hand, the FDA has recently declined approval

of pirfenidone for treatment of IPF and asked for additional and

stronger evidence of efficacy of pirfenidone in IPF. What are now

needed are data on mortality and overall survival, as well as quality

of life (QoL) on pirfenidone.

Data on single studies assessing eight other drugs have also been

included in this updated version of the review. In particular, the

findings of IFIGENIA assessing the effects of N-acetylcysteine in

combination with prednisone and azathioprine, as compared to

combined prednisone and azathioprine, merit some discussion.

With regard to study methodology, the findings of this trial are

weakened by the lack of a true placebo arm, since patients in the

placebo arm were all treated with a combination of prednisone and

azathioprine: fortunately, a specifically designed RCT (the PAN-

THER trial) directly comparing N-acetylcysteine with placebo

is currently ongoing in the United States in the context of the

’IPFnet’ clinical trial network. On the other hand, a recently pub-

lished analysis of the data set generated by the IFIGENIA trial

(Behr 2009) suggests that, when considering the subgroup of pa-

tients who completed the trial, pulmonary function did not signif-

icantly change in the arm treated with N-acetylcysteine, whereas

most functional indices deteriorated in the arm not including N-

acetylcysteine and treated with prednisone and azathioprine only;

in addition, many of the categorical analyses of VC and DLCO

showed favourable changes with N-acetylcysteine. These findings,

although interesting and likely to generate new hypotheses, are

fully based on post hoc descriptive analyses and, as such, the body

of evidence identified for N-acetylcysteine does not currently per-

mit robust conclusions regarding its effect in modifying the natu-

ral history of the disease. However, since this appears to be a safe

and well-tolerated drug, on the balance of probabilities it would

be reasonable to offer it to patients until definitive trial data are

available in the near future.

The efficacy and the safety of the anticoagulant drug warfarin

has been assessed in a small randomised, multicentre clinical trial

in Japan (Kubo 2005). The primary endpoints (overall survival

and hospitalisation-free period) showed a significant difference in

survival between the two study groups favouring anticoagulant

therapy: mortality associated with acute exacerbations of IPF was

significantly reduced in the anticoagulant group as compared to

the non-anticoagulant group, while the two groups did not sig-

nificantly differ in terms of hospitalisation-free periods. Although

these findings look promising, some methodological issues pre-

vented a precise assessment of the benefit of warfarin effect in

IPF. In particular, the high rate of IPF exacerbations might reflect

unusually high rates of hospitalisation of patients with different

characteristics of IPF natural history in Japan. The considerable

early withdrawal in the warfarin arm and its possible impact on

the randomisation process (due to a lack of an intention-to-treat

approach) as well as the lack of a true placebo arm may have biased

the study result. As for N-acetylcysteine, the IPFnet is running a

RCT assessing warfarin in a study with a placebo-controlled de-

sign, and given the potential side effects of anticoagulation it may

be prudent to await these results before routinely offering warfarin

to IPF patients.

The recombinant soluble human TNF-alpha receptor etanercept,

a TNF antagonist, has been evaluated in a randomised, prospec-

tive, double-blind, placebo-controlled, multicentre trial (Raghu

2008): primary endpoints (change in the percentage of predicted

FVC or DLCO, and in the P(A-a)O2 at rest) were not affected

and, as such, the trial did not provide evidence for an effect of this

drug in physiological outcomes associated with IPF. Nonetheless,

the study only enrolled a relatively small population and since the

results suggest that this drug has a favourable safety profile, a larger

study is justified before a positive effect can be ruled out defini-

tively.

Imatinib, a tyrosine kinase inhibitor, has been evaluated in a phase

II, randomised, double-blind, placebo-controlled study (Daniels

2010) on 119 IPF patients. The primary outcome (a combined

measure of disease progression or death) did not reach statistical

significance. Other studies on multiple tyrosine kinase inhibitors

are ongoing and the results of one phase II randomised, double-

blind, placebo-controlled trial are expected to be available in late

2010.

Bosentan is an antagonist of endothelin-1 A and B receptors, and

because of the pro-fibrotic effects of endothelin-1 receptor activa-

tion, it has been hypothesised that bosentan might have benefi-

cial effects in IPF. A double-blind, placebo-controlled multicentre

trial (BUILD 1) assessed the effect of bosentan on change in exer-

cise capacity, as measured by a modified six-minute walking test.

Bosentan showed no superiority over placebo; however, an appar-

ently rather arbitrary post hoc analysis showed a trend in favour

of bosentan with respect to time to death or disease progression

in patients diagnosed by surgical lung biopsy. Based upon these

findings, a large phase III trial (BUILD 3) has been conducted:

recently, the sponsor has released the preliminary results of this

trial, showing that the primary endpoint (reduction in morbidity/

mortality) was not significantly different between the two study

groups (P = 0.21). Although the results of the BUILD trials do not

provide evidence for an effect of bosentan in IPF, a further study

on 150 IPF patients treated with the new endothelin receptor an-

tagonist macitentan, is currently enrolling patients.

Overall completeness and applicability ofevidence

Despite encouraging data from the original trial on interferon

gamma-1beta included in the previous version of this systematic

review, none of subsequent studies of this drug included in this up-

dated review provided further evidence in support of the original



findings. Evidence for the use of azathioprine remains limited to

one RCT (Raghu 1991) showing a small but statistically significant

long-term survival advantage for azathioprine once allowance was

made for age differences. One study (Douglas 1998) showed that

colchicine is no more effective as a treatment than prednisone, with

no significant difference in outcomes; cyclophosphamide contin-

ues to have very limited evidence for use in IPF patients (Johnson

1989). The evidence available for any of these drugs is probably

insufficient to support their clinical use.The most commonly used

combination in IPF of azathioprine plus prednisolone has still not

been tested against placebo therapy.

As outlined above, this review might be affected by some poten-

tial biases, although most of them are outside of control of the

authors, being related to the data provided by the pharmaceutical

companies sponsoring the pirfenidone trials. It is highly likely that

all relevant studies were identified and included in the review, al-

though probably not all relevant data has been obtained, especially

on survival/mortality and QoL. Nonetheless, unpublished results

on pirfenidone have also been publicly disclosed in the context

of the FDA evaluation of the drug (Sponsor’s Briefing Document

2010). We shall undertake a careful re-evaluation of the data on

pirfenidone after full publication of the two currently unpublished

trials (CAPACITY 1; CAPACITY 2).

Quality of the evidence

As outlined above, this review might be affected by some poten-

tial biases, although most of them are outside of control of the

authors, being related to the data provided by the pharmaceutical

companies sponsoring the pirfenidone trials.

Potential biases in the review process

It is highly likely that all relevant studies were identified and

included in the review, although probably not all relevant data

have been obtained, especially on survival/mortality and QoL.

Nonetheless, unpublished results on pirfenidone have also been

publicly disclosed in the context of the FDA evaluation of the drug

(Sponsor’s Briefing Document 2010). We shall undertake a careful

re-evaluation of the data on pirfenidone after full publication of

the two currently unpublished trials (CAPACITY 1; CAPACITY

2).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

The meta-analyses performed in this updated review on non-

steroid drugs to treat IPF showed no evidence for a beneficial ef-

fect of interferon gamma-1beta based on two large randomised

trials. On the other hand, for pirfenidone, a meta-analysis of three

large randomised trials showed evidence of a beneficial effect: in

particular, the size of the effect on progression-free survival, a pa-

tient-important outcome, suggests a clinically relevant benefit for

patients. However, our meta-analysis on pirfenidone for IPF was

mainly based on unpublished data. In addition, based on available

data, which include the full results of the CAPACITY 1 and 2

trials, the FDA has denied approval of pirfenidone for treatment

of IPF and asked for an additional clinical trial: pirfenidone is also

currently under evaluation in Europe. In any case, at this moment

additional data on mortality and quality of life with pirfenidone

are needed and should be considered in future systematic reviews.

The positive findings for N-acetylcysteine should be regarded as

provisional considering the lack of a true placebo arm and the

limited follow up of the study sample. Since at the time of this

update pirfenidone has not been approved for clinical use in most

countries, except Japan, enrolment in placebo-controlled clinical

trials still remains a valid option for patients with IPF. The level of

evidence available for other drugs, including warfarin, bosentan,

imatinib and etanercept, is insufficient to allow any firm conclu-

sion on their use in clinical practice, although some of these drugs

merit further investigation.

Implications for research

Further research is needed to clarify the natural history of IPF,

with particular emphasis on different clinical phenotypes, based

on differences in survival, rates of acute exacerbations, ethnicity

and co-morbidities (e.g. pulmonary arterial hypertension). Re-

search to assess the real burden of disease in different geographic

regions will also be needed. In this context, the creation or the

extension of supra-national research networks is certainly needed.

Although continuously increasing, the current evidence to treat

these patients is limited. There are no prognostic factors which

have been extensively validated in prospective studies and there-

fore biomarkers cannot be used to select subgroups with different

survival in randomised controlled trials. Since no new drugs have

been approved for use at the moment, except for Japan, further tri-

als need to be placebo-controlled and the use of ’routine care’ only

in the comparator arm should be discouraged. It has to be noted

that the use of post hoc analyses to identify ’responder’ groups to

be included in future trials have largely been arbitrary and this

practice should be avoided. Given the progressive nature of the

disease, researchers will need to show improvements in overall sur-

vival or progression-free survival, although other surrogate mark-

ers (e.g. FVC) might help to assess potential efficacy in smaller and

essentially pilot studies. For these surrogate endpoints it should

become important and routine to report results using statistical

analysis that may allow some informal assessment of replication if

not combination of data in meta-analyses. Future research should

focus on large suitably powered placebo-controlled trials assessing

the effect of drugs on clinically relevant endpoints (ideally overall



survival), with a duration of intervention of at least nine to 18

months and with pre-specified statistical analyses based on an in-

tention-to-treat design. To obtain sufficient recruits in such studies

national or even inter-national collaborative studies are necessary,

and smaller studies should be discouraged by Ethics and Research

Advisory committees.

The progressive nature of IPF implies that survival-related out-

comes should be the focus of intense clinical research. In particu-

lar, attention should be drawn in the future to the effect of therapy

on progression-free survival and categorical changes in functional

indices: additional data need to be generated to assess whether

such endpoints should become the standard measures in future

IPF clinical trials.

A C K N O W L E D G E M E N T S

The authors acknowledge the willingness of the companies Sh-

ionogi & Co. Ltd (Dr. Eiichi Yamaguchi) and Intermune, Inc

(Dr. Williamson Bradford) to provide additional and unpublished

data on pirfenidone studies. We also acknowledge Huw Davies for

his contribution to the previous version of this review and Toby

Lasserson and Emma Welsh for their invaluable editorial assis-

tance.

R E F E R E N C E S

References to studies included in this review

Azuma 2005 {published data only}

Azuma A, Nukiwa T, Tsuboi E, Suga M, Abe S, Nakata K, et

al.Double-blind, placebo-controlled trial of pirfenidone in patients

with idiopathic pulmonary fibrosis. American Journal of Respiratory

and Critical Care Medicine 2005;171(9):1040–7.

BUILD 1 {published data only}

King TE Jr, Behr J, Brown KK, du Bois RM, Lancaster L, de

Andrade JA, et al.BUILD-1: A randomized placebo-controlled trial

of bosentan in idiopathic pulmonary fibrosis. American Journal of

Respiratory and Critical Care Medicine 2008;177(1):75–81.

CAPACITY 1 {unpublished data only}

A randomised, double-blind, placebo-controlled, phase III study of

the safety and efficacy of pirfenidone in patients with idiopathic

pulmonary fibrosis. Data on file.

CAPACITY 2 {unpublished data only}

A randomised, double-blind, placebo-controlled, phase III, three-

arm study of the safety and efficacy of pirfenidone in patients with

idiopathic pulmonary fibrosis. Data on file.

Daniels 2010 {published data only}

Daniels CE, Lasky JA, Limper AH, Mieras K, Gabor E, Schroeder

DR, et al.Imatinib treatment for idiopathic pulmonary fibrosis.

Randomized placebo-controlled trial results. American Journal of


Douglas 1998 {published data only}

Douglas WW, Ryu JH, Swensen SJ, Offord KP, Schroeder DR,

Caron GM, et al.Colchicine versus prednisone in the treatment of

idiopathic pulmonary fibrosis. American Journal of Respiratory and

Critical Care Medicine 1998;158(1):220–5.

IFIGENIA {published data only}

Behr J, Demedts M, Buhl R, Costabel U, Dekhuijzen RP, Jansen

HM, et al.Lung function in idiopathic pulmonary fibrosis -

extended analyses of the IFIGENIA trial. Respiratory Research 2009;

10:101.∗ Demedts M, Behr J, Buhl R, Costabel U, Dekhuijzen R, Jansen

HM, et al.High-dose acetylcysteine in idiopathic pulmonary

fibrosis. New England Journal of Medicine 2005;353(21):2229–42.

INSPIRE {published data only}

King TE Jr, Albera C, Bradford WZ, Costabel U, Hormel P,

Lancaster L, et al.Effect of interferon gamma-1b on survival in

patients with idiopathic pulmonary fibrosis (INSPIRE): a

multicentre, randomised, placebo-controlled trial. Lancet 2009;374

(9685):222–8.

Johnson 1989 {published data only}

Johnson MA, Kwan S, Snell NJC, Nunn AJ, Darbyshire JH,

Turner-Warwick M. Randomised controlled trial comparing

prednisolone alone with cyclophosphamide and low dose

prednisolone in combination in cryptogenic fibrosing alveolitis.

Thorax 1989;44(4):280–8.

Kubo 2005 {published data only}

Kubo H, Nakayama K, Yanai M, Suzuki T, Yamaya M, Watanabe

M, et al.Anticoagulant therapy for idiopathic pulmonary fibrosis.

Chest 2005;128(3):1475–82.

Raghu 1991 {published data only}

Raghu G, Depaso WJ, Cain K, Hammar SP, Wetzel CE, Dreis DF,

et al.Azathioprine combined with prednisone in the treatment of

idiopathic pulmonary fibrosis: a prospective double-blind,

randomized, placebo-controlled clinical trial. American Review of

Respiratory Disease 1991;144(2):291–6.


Raghu G, Brown KK, Bradford WZ, Starko K, Noble PW,

Schwartz DA, et al.A placebo-controlled trial of interferon gamma-

1b in patients with idiopathic pulmonary fibrosis. New England

Journal of Medicine 2004;350(2):125–33.


Raghu G, Brown KK, Costabel U, Cottin V, du Bois RM, Lasky JA,

et al.Treatment of idiopathic pulmonary fibrosis with etanercept:

an exploratory, placebo-controlled trial. American Journal of


Taniguchi 2010 {published and unpublished data}

Taniguchi H, Ebina M, Kondoh Y, Ogura T, Azuma A, Suga M, et

al.Pirfenidone in idiopathic pulmonary fibrosis. European

Respiratory Journal 2010;35(4):821–9.



Ziesche 1999 {published data only}

Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A

preliminary study of long-term treatment with interferon gamma-

1b and low-dose prednisolone in patients with idiopathic

pulmonary fibrosis. New England Journal of Medicine 1999;341

(17):1264–9.

References to studies excluded from this review

Alton 1989 {published data only}

Alton EWFW, Johnson M, Turner-Warwick M. Advanced

cryptogenic fibrosing alveolitis: preliminary report on treatment

with cyclosporin A. Respiratory Medicine 1989;83(4):277–9.

Antoniou 2006 {published data only}

Antoniou KM, Nicholson AG, Dimadi M, Malagari K, Latsi P,

Rapti A, et al.Long-term clinical effects of interferon gamma-1b

and colchicine in idiopathic pulmonary fibrosis. European

Respiratory Journal 2006;28(3):496–504.

Baughman 1992 {published data only}

Baughman RP, Lower EE. Use of intermittent intravenous

cyclophosphamide for idiopathic pulmonary fibrosis. Chest 1992;

102(4):1090–4.

Behr 1993 {published data only}

Behr J, Adelmann-Grill BC, Krombach F, Beinert T, Schwaiblmair

M, Fruhmann G. Fibroblast chemotactic response elicited by native

bronchoalveolar lavage fluid from patients with fibrosing alveolitis.

Thorax 1993;48(7):736–42.

Behr 1997 {published data only}

Behr J, Maier K, Degenkolb B, Krombach F, Vogelmeier C.

Antioxidative and clinical effects of high-dose N-acetylcysteine in

fibrosing alveolitis. Adjunctive therapy to maintenance

immunosuppression. American Journal of Respiratory and Critical

Care Medicine 1997;156(6):1897–901.

Brown 1971 {published data only}

Brown CH, Turner-Warwick M. The treatment of cryptogenic

fibrosing alveolitis with immunosuppressant drugs. Quarterly

Journal of Medicine 1971;40(158):289–302.

Cegla 1974 {published data only}

Cegla UH, Meier-Sydow J, Kroidl R, Kronenberger H. High

dosages of D-penicillamine in pulmonary fibroses [Hochdosierte

D–penicillamintherapie (3.6g/die) bei lungfibrosen].

Pneumonologie 1974;150(2-4):261–9.


Cegla UH, Kroidl RF, Meier-Sydow J, Thiel C, Czarnecki G,

Schreiber F. Therapy of idiopathic fibrosis of the lung.

Pneumonolgie 1975;152(1-3):75–92.


Cegla UH. Treatment of idiopathic fibrosing alveolitis: therapeutic

experiences with azathioprine-prednisolone and D-penicllamine-

prednisolone combination therapy [Behandlung der idiopathisch

fibrosier–ender Alveolitis]. Schweizerische Medizinische

Wochenschrift 1977;107(6):184–7.


Cegla UH. [Neure schemen fur die therapie der idiopathisch

fibrosierenden alveolitis]. In: Forschbach C editor(s). Fortbildung

in thoraxkrankhealth 8(?). Stuttgart: Hippokrates Verlag, 1978:

215–7.

Collard 2004 {published data only}

Collard HR, Ryu JH, Douglas WW, Schwarz MI, Curran-Everett

D, King TE Jr, et al.Combined corticosteroid and

cyclophosphamide therapy does not alter survival in idiopathic

pulmonary fibrosis. Chest 2004;125(6):2169–74.

Costabel 1981 {published data only}

Costabel U, Matthys H. Different therapies and factors influencing

response to therapy in idiopathic diffuse fibrosing alveolitis.

Respiration 1981;42(3):141–9.

Dayton 1993 {published data only}

Dayton CS, Schwartz DA, Helmers RA, Pueringer RJ, Gilbert SR,

Merchant RK, et al.Outcome of subjects with idiopathic

pulmonary fibrosis who fail corticosteroid therapy. Implications for

further studies. Chest 1993;103(1):69–73.


Douglas WW, Ryu JH, Bjoraker JA, Schroeder DR, Myers JL,

Tazelaar HD, et al.Colchicine versus prednisone as treatment of

usual interstitial pneumonia. Mayo Clinic Proceedings 1997;72(3):

201–9.


Douglas WW, Ryu JH, Scroeder DR. Idiopathic pulmonary

fibrosis: impact of oxygen and colchicine, prednisone, or no

therapy on survival. American Journal of Respiratory and Critical

Care Medicine 2000;161(4 Pt 1):1172–8.


Douglas WW, Ryu JH, Schroeder DR. Idiopathic pulmonary

fibrosis: survival as a function of oxygen therapy and treatment

program. Chest 2001;120(Suppl):62S.

Eliasson 1985 {published data only}

Eliasson O, Cole SR, Degraff A. Adverse effects of

cyclophosphamide in idiopathic pulmonary fibrosis. Connecticut

Medicine 1985;49(5):286–9.

Fukazawa 1990 {published data only}

Fukazawa M, Kawano M, Hisano S, Ueda K, Matsuba K. Efficacy

of cyclosporine A for idiopathic pulmonary fibrosis. European

Journal of Paediatrics 1990;149(6):441–2.

Fulmer 1978 {published data only}

Fulmer J, Elson N, Von Gal E, et al.Treatment of idiopathic

pulmonary fibrosis. Clinical Research 1978;26:538A.

Garcia 1998 {published data only}

Garcia JEL, Rodriguez FM, Lopez AJ, et al.Effect of cyclosporin A

on inflammatory cytokine production by human alveolar

macrophages. Respiratory Medicine 1998;92:722–8.

Goodman 1978 {published data only}

Goodman M, Turner-Warwick M. Pilot study of penicillamine

therapy in corticosteroid failure patients with widespread

pulmonary fibrosis. Chest 1978;74(3):338.

Goodman 1981 {published data only}

Goodman M, Knight RK, Turner-Warwick M. Pilot studies of

penicillamine therapy in steroid failure patients with interstitial

lung disease. In: Maini RN, Berry H editor(s). Modulation of

autoimmunity and disease. Prague: Praeger, 1981:291–300.



Gross 1973 {published data only}

Gross K, Unholtz K. D-penicillamine in the treatment of

pulmonary fibrosis [Therapeutische Beeinflussung der

Bindegewebswcherung bei Lungenfibrosen]. Pneumonologie 1973;

148(3):201–7.

Haslam 1980 {published data only}

Haslam PL, Turton CWG, Lukoszek A, Salsbury AJ, Dewar A,

Collins JV, et al.Bronchoalveolar lavage fluid cell counts in

cryptogenic fibrosing alveolitis and their relation to therapy. Thorax

1980;35(5):328–39.

Homolka 2001 {unpublished data only}

Homolka J, Svobodova L, Slovakova A. Cyclosporine A in the

treatment of idiopathic pulmonary fibrosis/usual interstitial

pneumonia. American Thoracic Society meeting. 2001.

Kalra 2003 {published data only}

Kalra S, Utz JP, Ryu JH, Mayo Clinic Interstitial Lung Diseases

Group. Interferon gamma-1b therapy for advanced idiopathic

pulmonary fibrosis. Mayo Clin Proceedings 2003;78(9):1082–7.

Kolb 1998 {published data only}

Kolb M, Kirschner J, Riedel W, Wirtz H, Schmidt M.

Cyclophosphamide pulse therapy in idiopathic pulmonary fibrosis.

European Respiratory Journal 1998;12(6):1409–14.

Kondoh 2005 {published data only}

Kondoh Y, Taniguchi H, Yokoi T, Nishiyama O, Ohishi T, Kato T,

et al.Cyclophosphamide and low-dose prednisolone in idiopathic

pulmonary fibrosis and fibrosing nonspecific interstitial

pneumonia. European Respiratory Journal 2005;25(3):528–33.

Liebetrau 1982 {published data only}

Liebetrau G, Pielesch W, Ganguin HG, Jung A, Jung H. Therapy

of pulmonary fibrosis with D-penicillamine [Die Therapie der

lungenfibrosen mit D–penizillamin]. Zeitschrift fur die gesamte

innere Medizin und ihre Grenzgebiete 1982;37(9):263–6.

Meier-Sydow 1970 {published data only}

Meier-Sydow J, Schmidt W, Schnabel KH, et al.[Die

Immunosuppressive therapie von lungenerkrangungen].

Verhandlungen der Deutschen Gesellschaft fur Innere Medezin 1970;

76:107–11.


Meier-Sydow J, Rust M. [Aussage der Lungenfunktionsanalyse uber

den Verlauf diffuser fibrosiender interstitieller

Lungenerkrankungen]. In: Hamm, J editor(s). Interstitielle

Lungenerkrankungen, Lungenfibrosen. Stuttgart: Thieme, 1975:

76–88.


Meier-Sydow J, Rust M, Kronenberger H, Thiel C, Amthor M,

Riemann H. Long-term follow-up of lung function with

parameters in patients with idiopathic pulmonary fibrosis treated

with prednisone and azathioprine or D-penicillamine

[Langzeitbeobachtung von lungfunktionsparametern bei

Lungfibrosen unter prednison und azathioprin oder

D–penicllamin]. Praxis und Klinik der Pneumologie 1979;33(Suppl

1):680–8.


Meier-Sydow J, Rust M, Kronenberger H, Krempel. Survival of

patients with idiopathic pulmonary fibrosis following treatment

with azathioprine, D-penicillamine or prednisolone: ten year

follow-up. Chest 1990;98:18S.

Meuret 1978 {published data only}

Meuret G, Fueter R, Gloor F. Early stage of fulminant idiopathic

pulmonary fibrosis cured by intense combination therapy using

cyclophosphamide, vincristine, and prednisone. Respiration 1978;

36(4):228–33.

Meyer 1994 {published data only}

Meyer A, Buhl R, Magnussen H. The effect of oral N-acetylcysteine

on lung glutathione levels in idiopathic pulmonary fibrosis.

European Respiratory Journal 1994;7(3):431–6.

Meyer 1995 {published data only}

Meyer A, Buhl R, Kampf S, Magnussen H. Intravenous N acetyl-

cysteine and lung glutathione of patients with pulmonary fibrosis

and normals. American Journal of Respiratory and Critical Care

Medicine 1995;152(3):1055–60.

Moolman 1991 {published data only}

Moolman JA, Bardin PG, Rossouw DJ, Joubert JR. Cyclosporin as

a treatment for interstitial lung disease of unknown aetiology.

Thorax 1991;46(8):592–5.

Nadrous 2004 {published data only}

Nadrous HF, Ryu JH, Douglas WW, Decker PA, Olson EJ. Impact

of angiotensin-converting enzyme inhibitors and statins on survival

in idiopathic pulmonary fibrosis. Chest 2004;126(2):438–46.

O’Donnell 1987 {published data only}

O’Donnell K, Keogh B, Cantin A, Crystal RG. Pharmacologic

suppression of the neutrophil component of the alveolitis in

idiopathic pulmonary fibrosis. American Review of Respiratory

Disease 1987;136(2):288–92.

Pereira 2006 {published data only}

Pereira CA, Malheiros T, Coletta EM, Ferreira RG, Rubin AS, Otta

JS, et al.Survival in idiopathic pulmonary fibrosis - cytotoxic agents

compared to corticosteroids. Respiratory Medicine 2006;100(2):

340–7.

Peters 1993 {published data only}

Peters SG, McDougall JC, Douglas WW, Coles DT, DeRemee RA.

Colchicine in the treatment of pulmonary fibrosis. Chest 1993;103

(1):101–4.

Raghu 1999b {published data only}

Raghu G, Johnson WC, Lockhart D, Mageto Y. Treatment of

idiopathic pulmonary fibrosis with a new antifibrotic agent,

pirfenidone. American Journal of Respiratory and Critical Care

Medicine 1999;159(4 Pt 1):1061–9.

Roig 2010 {published data only}

Roig V, Herrero A, Arroyo-Cózar M, Vielba D, Juarros S, Macías E.

Comparative study between oral azathioprine and intravenous

cyclophosphamide pulses in the treatment of idiopathic pulmonary

fibrosis [Estudio comparativo entre azatioprina oral y pulsos

intravenosos de ciclofosfamida en el tratamiento de la fibrosis

pulmonar idiopática]. Archivos de Bronconeumología 2010;46(1):

15–9.

Rudd 1981 {published data only}

Rudd RM, Haslam PL, Turner-Warwick M. Cryptogenic fibrosing

alveolitis - relationships of pulmonary physiology and



bronchoalveolar lavage to response to treatment and prognosis.

American Review of Respiratory Disease 1981;124(1):1–8.

Rust 1980 {published data only}

Rust M, Meier-Sydow J. [Weitre Untersuchungen uber die

Langzeitprognose der idiopathischen Lungenfibrose unter therapie

mit Azathioprin oder D–penicillamin und Prednison].

Verhandlungen der Deutschen Gesellschaft fur Innere Medezin 1980;

86:?.

Schlehe 1973 {published data only}

Schlehe H, Konietzko N, Altenstetter F, Matthys H. Therapy of

idiopathic diffuse pulmonary fibrosis [Therapie der idiopathischen

diffusen lungenfibrosen]. Schweizerische Medizinische Wochenschrift

1973;103(44):1543–7.

Schulz 1978 {published data only}

Schulz G. Treatment of diffuse lung fibrosis with D-penicillamine

[Die Behandlung diffuser Lungenfibrosen mit D–Penicillamin].

Zeitschrift fur die gesamte innere Medizin und ihre Grenzgebiete

1978;33(21):784–9.

Schwartz 1994 {published data only}

Schwartz DA, Van Fossen DS, Davis CS, Helmers RA, Dayton CS,

Burmeister LF, et al.Determinants of progression in idiopathic

pulmonary fibrosis. American Journal of Respiratory and Critical

Care Medicine 1994;149(2 Pt 1):444–9.

Selman 1998 {published data only}

Selman M, Carrillo G, Salas J, Padilla RP, Pérez-Chavira R,

Sansores R, et al.Colchicine, D-penicillamine and prednisone in the

treatment of idiopathic pulmonary fibrosis. Chest 1998;114(2):

507–12.

Shishido 1992 {published data only}

Shishido M, Ichiki H, Yano M, Toda K, Ohtsuki Y. A case of

idiopathic pulmonary fibrosis with histology of usual interstitial

pneumonia that responded to pulse therapy followed by combined

immunosuppression with prednisolone and azathioprine. Japanese

Journal of Thoracic Disease 1992;30:2139–45.

Turner-Warwick 1987 {published data only}

Turner-Warwick M, Haslam PL. The value of serial

bronchoalveolar lavages in assessing the clinical progress of patients

with cryptogenic fibrosing alveolitis. American Review of Respiratory

Disease 1987;135(1):26–34.

Undurraga 1998 {published data only}

Undurraga AP, Meneses MC, Sabbah EP, Oyarzun MG. Treatment

of idiopathic pulmonary fibrosis with colchicine [Tratamiento de la

fibrosis pulmonar idiopatica con colchicina]. Revista Medica de

Chile 1998;126(11):1345–53.

Van Oortegem 1994 {published data only}

Van Oortegem K, Wallaert B, Marquette CH, Ramon P, Perez T,

Lafitte JJ, et al.Determinants of response to immunosuppressive

therapy in idiopathic pulmonary fibrosis. European Respiratory

Journal 1994;7(11):1950–7.

Venuta 1993 {published data only}

Venuta F, Rendina EA, Ciriaco P, De Giacomo T, Pompeo E,

Bachetoni A, et al.Efficacy of cyclosporine to reduce steroids in

patients with idiopathic pulmonary fibrosis before lung

transplantation. Journal of Heart and Lung Transplantation 1993;12

(6 Pt 1):909–14.

Weese 1975 {published data only}

Weese WC, Levine BW, Kazemi H. Interstitial lung disease resistant

to corticosteroid therapy. Report of three cases treated with

azathioprine or cyclophosphamide. Chest 1975;67(1):57–60.

Winterbauer 1978 {published data only}

Winterbauer RH, Hammar SP, Hallman KO, Hays JE, Pardee NE,

Morgan HE, et al.Diffuse interstitial pneumonitis.

Clinicopathologic correlations in 20 patients treated with

prednisone/azathioprine. American Journal of Medicine 1978;65(4):

661–72.

Xaubet 2001 {published data only}

Xaubet A, Agustí C, Luburich P, Roca J, Ayuso MC, Marrades RM,

et al.Is it necessary to treat all patients with idiopathic pulmonary

fibrosis?. Sarcoidosis, Vasculitis, and Diffuse Lung Disease 2001;18

(3):289–95.

Ziesche 1996 {published data only}

Ziesche R, Kink E, Herold C, et al.Therapy of chronic interstitial

lung disease with a combination of interferon-gamma and low dose

prednisolone. Chest 1996;110:25S.

Zisman 2000 {published data only}

Zisman DA, Lynch JP, Toews GB, Kazerooni EA, Flint A, Martinez

FJ. Cyclophosphamide in the treatment of idiopathic fibrosis: a

prospective study in patients who failed to respond to

corticosteroids. Chest 2000;117(6):1619–26.

References to ongoing studies

ACE-IPF {unpublished data only}

AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis.

Ongoing study 2009.

ARTEMIS-IPF {unpublished data only}

Randomized, Placebo-Controlled Study to Evaluate Safety and

Effectiveness of Ambrisentan in IPF. Ongoing study December

2008.

BUILD-3 {unpublished data only}

BUILD 3: Bosentan Use in Interstitial Lung Disease. Ongoing

study November 2006.

PANTHER-IPF {unpublished data only}

Evaluating the Effectiveness of Prednisone, Azathioprine, and N-

acetylcysteine in People With Idiopathic Pulmonary Fibrosis.

Ongoing study October 2009.

STEP-IPF {unpublished data only}

Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary

Fibrosis. Ongoing study August 2007.

TOMORROW {unpublished data only}

Safety And Efficacy of BIBF 1120 in Idiopathic Pulmonary Fibrosis

(the TOMORROW trial). Ongoing study August 2007.

Additional references

Arase 2003

Arase Y, Ikeda K, Tsubota A, Saitoh S, Suzuki Y, Kobayashi M, et

al.Usefulness of serum KL-6 for early diagnosis of idiopathic

pulmonary fibrosis in patients with hepatitis C virus. Hepatology

Research 2003;27(2):89–94.



ATS 2000

American Thoracic Society. Idiopathic pulmonary fibrosis:

diagnosis and treatment. American Journal of Respiratory and

Critical Care Medicine 2000;161(2 Pt 1):646–64.

ATS 2002

American Thoracic Society. Classification of the idiopathic

interstitial pneumonias. American Journal of Respiratory and Critical

Care Medicine 2002;65(2):277–304.

Behr 2009

Behr J, Demedts M, Buhl R, Costabel U, Dekhuijzen RP, Jansen

HM, et al.Lung function in idiopathic pulmonary fibrosis -

extended analyses of the IFIGENIA trial. Respiratory Research 2009;

10:101.

BTS 2008

Bradley B, Branley HM, Egan JJ, Greaves MS, Hansell DM,

Harrison NK, et al.Interstitial lung disease guideline: the British

Thoracic Society in collaboration with the Thoracic Society of

Australia and New Zealand and the Irish Thoracic Society. Thorax

2008;63 Suppl 5:v1–58.

Cantin 1987

Cantin AM, North SL, Fells GA, Hubbard RC, Crystal RG.

Oxidant-mediated epithelial cell injury in idiopathic pulmonary

fibrosis. Journal of Clinical Investigation 1987;79(6):1665–73.

Cantin 1989

Cantin AM, Hubbard RC, Crystal RG. Glutathione deficiency in

the epithelial lining fluid of the lower respiratory tract in idiopathic

pulmonary fibrosis. American Review of Respiratory Disease 1989;

139(2):370–2.

Chan-Yeung 1997

Chan-Yeung M, Müller NL. Cryptogenic fibrosing alveolitis.

Lancet 1997;350(9078):651–6.

Checa 2008

Checa M, Ruiz V, Montano M, Velazquez-Cruz R, Selman M,

Pardo A. MMP-1 polymorphisms and the risk of idiopathic

pulmonary fibrosis. Human Genetics 2008;124(5):465–472.

Churg 2007

Churg A, Muller NL, Silva CIS, Wright JL. Acute exacerbation

(acute lung injury of unknown cause) in UIP and other forms of

fibrotic interstitial pneumonias. American Journal of Surgical

Pathology 2007;31(2):277–84.

Collard 2007

Collard HR, Moore BB, Flaherty KR, Brown KK, Kaner RJ, King

TE, et al.Acute exacerbations of idiopathic pulmonary fibrosis.

American Journal of Respiratory Critical Care Medicine 2007;176(7):

636–43.

Coultas 1994

Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The

epidemiology of interstitial lung diseases. American Journal of


Du Bois 2009

Du Bois R, Albera C, Bradford W, Costabel U, Hormel P, King T

Jr, et al.Predictors of mortality in patients with idiopathic

pulmonary fibrosis (IPF). American Journal of Respiratory and

Critical Care Medicine. 2009; Vol. 179:A1114.

Du Bois 2010

Du Bois RM. Strategies for treating idiopathic pulmonary fibrosis.

Nature Reviews. Drug Discovery 2010;9:129–40.

Egan 1997

Egan JJ, Woodcock AA, Stewart JP. Viruses and idiopathic

pulmonary fibrosis. European Respiratory Journal 1997;10(7):

1433–7.

Falfan-Valencia 2005

Falfán-Valencia R, Camarena A, Juárez A, Becerril C, Montaño M,

Cisneros J, et al.Major histocompatibility complex and alveolar

epithelial apoptosis in idiopathic pulmonary fibrosis. Human

Genetics 2005;118(2):235–44.

Gauldie 2008

Gauldie J, Kolb M. Animal models of pulmonary fibrosis: how far

from effective reality?. American Journal of Physiology. Lung Cellular

and Molecular Physiology 2008;294(2):L151.

Gribbin 2006

Gribbin J, Hubbard RB, Le Jeune I, Smith CJ, West J, Tata LJ.

Incidence and mortality of idiopathic pulmonary fibrosis and

sarcoidosis in the UK. Thorax 2006;61(11):980–5.

Hansell 2008

Hansell DM, Bankier AA, Macmahon H, McLoud TC, Muller NL,

Remy J. Fleischner Society Glossary of terms for thoracic imaging.

Radiology 2008;246(3):697–722.

Hanson 1976

Hanson RR, Zavala DC, Rhodes ML, Keim LW, Smith JD.

Transbronchial biopsy via flexible fiberoptic bronchoscopy: results

in 164 patients. American Review of Respiratory Disease 1976;114

(1):67–72.

Hardie 2009

Hardie WD, Glasser SW, Hagood JS. Emerging concepts in the

pathogenesis of lung fibrosis. The American Journal of Pathology

2009;175(1):3–16.

Higgins 2008

Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews

of Interventions Version 5.0.2 [updated September 2009]. The

Cochrane Collaboration, 2008. Available from www.cochrane-

handbook.org.

Hubbard 1996

Hubbard R, Lewis S, Richards K, Johnston I, Britton J.

Occupational exposure to metal or wood dust and aetiology of

cryptogenic fibrosing alveolitis. Lancet 1996;347(8997):284–9.

Hubbard 1998

Hubbard R, Johnston I, Britton J. Survival in patients with

cryptogenic fibrosing alveolitis: a population-based cohort study.

Chest 1998;113(2):396–400.

Hubbard 2000

Hubbard R, Cooper M, Antoniak M, Venn A, Khan S, Johnston I,

et al.Risk of cryptogenic fibrosing alveolitis in metal workers.

Lancet 2000;355(9202):466–7.

Hunninghake 2001

Hunninghake GW, Zimmerman MB, Schwartz DA, King TE Jr,

Lynch J, Hegele R, et al.Utility of a lung biopsy for the diagnosis of

idiopathic pulmonary fibrosis. American Journal of Respiratory and

Critical Care Medicine 2001;164(2):193–6.



Iwai 1994

Iwai K, Mori T, Yamada N, Yamaguchi M, Hosoda Y. Idiopathic

pulmonary fibrosi. Epidemiologic approaches to occupational

exposure. American Journal of Respiratory and Critical Care Medicine

1994;150(3):670–5.

Johkoh 1999

Johkoh T, Muller NL, Cartier Y, Kavanagh PV, Hartman TE, Akira

M, et al.Idiopathic interstitial pneumonias: diagnostic accuracy of

thin-section CT in 129 patients. Radiology 1999;211(2):555–60.

Juni 2001

Juni P, Altman DG, Egger M. Systematic reviews in health care:

assessing the quality of controlled clinical trials. BMJ 2001;323

(7303):42–6.

Karakatsani 2009

Karakatsani A, Papakosta D, Rapti A, Antoniou KM, Dimadi M,

Markopoulou A, et al.Epidemiology of interstitial lung diseases in

Greece. Respiratory Medicine 2009;103(8):1122–9.

Kelly 2002

Kelly BG, Lok SS, Hasleton PS, Egan JJ, Stewart JP. A rearranged

form of Epstein-Barr virus DNA is associated with idiopathic

pulmonary fibrosis. American Journal of Respiratory and Critical

Care Medicine 2002;166(4):510–3.

Kim 2006

Kim DS, Park JH, Park BK, Lee JS, Nicholson AG, Colby T. Acute

exacerbation of idiopathic pulmonary fibrosis: frequency and

clinical features. European Respiratory Journal 2006;27(1):143–50.

King 2005

King TE Jr, Safrin S, Starko KM, Brown KK, Noble PW, Raghu G,

et al.Analyses of efficacy end points in a controlled trial of

interferon gamma-1b for idiopathic pulmonary fibrosis. Chest

2005;127:171–7.

Kondoh 1993

Kondoh Y, Taniguchi H, Kawabata Y, Yokoi T, Suzuki K, Takagi K.

Acute exacerbation in idiopathic pulmonary fibrosis. Analysis of

clinical and pathologic findings in three cases. Chest 1993;103(6):

1808–12.

Lee 2005

Lee H, Ryu JH, Wittmer MH, Hartman TE, Lymp JF, Tazelaar

HD, et al.Familial idiopathic pulmonary fibrosis: clinical features

and outcome. Chest 2005;127(6):2034–41.

Lok 2001

Lok SS, Stewart JP, Kelly BG, Hasleton PS, Egan JJ. Epstein-Barr

virus and wild p53 in idiopathic pulmonary fibrosis. Respiratory

Medicine 2001;95(10):787–91.

MacNee 1995

NacNee W, Rahman I. Oxidants/antioxidants in idiopathic

pulmonary fibrosis. Thorax 1995;50 Suppl 1:S53–8.

Martinez 2005

Martinez FJ, Safrin S, Weycker D, Starko KM, Bradford WZ, King

TE Jr, et al.The clinical course of patients with idiopathic

pulmonary fibrosis. Annals of Internal Medicine 2005;142(12 Pt 1):

963–7.

Meliconi 1996

Meliconi R, Andreone P, Fasano L, Galli S, Pacilli A, Miniero R, et

al.Incidence of hepatitis C virus infection in Italian patients with

idiopathic pulmonary fibrosis. Thorax 1996;51(3):315–7.

Meltzer 2008

Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet

Journal of Rare Diseases 2008;3:8.

Miyake 2005

Miyake Y, Sasaki S, Yokoyama T, Chida K, Azuma A, Suda T, et

al.Occupational and environmental factors and idiopathic

pulmonary fibrosis in Japan. Annals of Occupational Hygiene 2005;

49(3):259–65.

Moeller 2008

Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The

bleomycin animal model: a useful tool to investigate treatment

options for idiopathic pulmonary fibrosis?. International Journal of

Biochemistry & Cell Biology 2008;40(3):362–82.

Moher 1998

Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et

al.Does quality of reports of randomised trials affect estimates of

intervention efficacy reported in meta-analyses?. Lancet 1998;352

(9128):609–13.

Nishimura 1992

Nishimura K, Kitaichi M, Izumi T, Nagai S, Kanaoka M, Itoh H.

Usual interstitial pneumonia: histologic correlation with high-

resolution CT. Radiology 1992;182(2):337–42.

Noble 2009

Noble P, Albera C, Bradford W, Costabel U, Kardatzke D, King T

Jr, et al.The CAPACITY (CAP) Trials: Randomized, Double-

Blind, Placebo-Controlled, Phase III Trials of Pirfenidone (PFD) in

Patients with Idiopathic Pulmonary Fibrosis (IPF). American

Journal of Respiratory and Critical Care Medicine. 2009; Vol. 179:

A1129.

Parmar 1998

Parmar MB, Torri V, Stewart L. Extracting summary statistics to

perform meta-analyses of the published literature for survival

endpoints. Statistics in Medicine 1998;17:2815–34.

Raghu 1999a

Raghu G, Mageto YN, Lockhart D, Schmidt RA, Wood DE,

Godwin JD. The accuracy of the clinical diagnosis of new-onset

idiopathic pulmonary fibrosis and other interstitial lung diseases. A

prospective study. Chest 1999;116(5):1168–74.

Raghu 2006a

Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J,

et al.High prevalence of abnormal acid gastro-oesophageal reflux in

idiopathic pulmonary fibrosis. European Respiratory Journal 2006;

27(1):136–42.

Raghu 2006b

Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G.

Incidence and prevalence of idiopathic pulmonary fibrosis.

American Journal of Respiratory and Critical Care Medicine 2006;

174(7):810–6.

Richeldi 2003

Richeldi L, Davies HR, Ferrara G, Franco F. Corticosteroids for

idiopathic pulmonary fibrosis. Cochrane Database of Systematic

Reviews 2003, Issue 3. [DOI: 10.1002/14651858.CD002880]

Rosas 2007

Rosas IO, Ren P, Avila NA, Chow CK, Franks TJ, Travis WD, et

al.Early interstitial lung disease in familial pulmonary fibrosis.



American Journal of Respiratory and Critical Care Medicine 2007;

176(7):698–705.

Schulz 1995

Schulz KF, Chalmers I, Hayes RJ, Altman DG. Empirical evidence

of bias. Dimensions of methodological quality associated with

estimates of treatment effects in controlled trials. JAMA 1995;273

(5):408–12.

Scott 1990

Scott J, Johnston I, Britton J. What causes cryptogenic fibrosing

alveolitis? A case-control study of environmental exposure to dust.

BMJ 1990;301(6759):1015–7.

Shure 1987

Shure D. Fiberoptic bronchoscopy: diagnostic applications. Clinics

in Chest Medicine 1987;8(1):1–13.

Shure 1989

Shure D. Transbronchial biopsy and needle aspiration. Chest 1989;

95(5):1130–8.

Sponsor’s Briefing Document 2010

Sponsor’s Briefing Document for the FDA Pulmonary-Allergy

Drugs Advisory Committee Meeting (NDA 22-535). InterMune

Inc 9 March 2010.

Steele 2005

Steele MP, Speer MC, Loyd JE, Brown KK, Herron A, Slifer SH, et

al.Clinical and pathologic features of familial interstitial

pneumonia. American Journal of Respiratory and Critical Care

Medicine 2005;172(9):1146–52.

Stewart 1999

Stewart JP, Egan JJ, Ross AJ, Kelly BG, Lok SS, Hasleton PS, et

al.The detection of Epstein-Barr virus DNA in lung tissue from

patients with idiopathic pulmonary fibrosis. American Journal of

Respiratory and Critical Care Medicine 1999;159(4 Pt 1):1336–41.

Taskar 2006

Taskar VS, Coultas DB. Is idiopathic pulmonary fibrosis an

environmental disease?. Proceedings of the American Thoracic Society

2006;3(4):293–8.

Tobin 1998

Tobin RW, Pope CE 2nd, Pellegrini CA, Emond MJ, Sillery J,

Raghu G. Increased prevalence of gastroesophageal reflux in

patients with idiopathic pulmonary fibrosis. American Journal of


Tsukamoto 2000

Tsukamoto K, Hayakawa H, Sato A, Chida K, Nakamura H, Miura

K. Involvement of Epstein-Barr virus latent membrane protein 1 in

disease progression in patients with idiopathic pulmonary fibrosis.

Thorax 2000;55(11):958–61.

Visscher 2006

Visscher DW, Myers JL. Histologic spectrum of idiopathic

interstitial pneumonias. Proceedings of the American Thoracic Society

2006;3(4):322–9.

Watters 1986

Watters LC, King TE, Schwarz MI, Waldron JA, Stanford RE,

Cherniack RM. A clinical, radiographic, and physiologic scoring

system for the longitudinal assessment of patients with idiopathic

pulmonary fibrosis. American Review of Respiratory Disease 1986;

133(1):97–103.

Wells 2003

Wells AU, Desai SR, Rubens MB, Goh NS, Cramer D, Nicholson

AG, et al.Idiopathic pulmonary fibrosis: a composite physiologic

index derived from disease extent observed by computed

tomography. American Journal of Respiratory and Critical Care

Medicine 2003;167:962–9.

Zuo 2002

Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, et

al.Gene expression analysis reveals matrilysin as a key regulator of

pulmonary fibrosis in mice and humans. Proceedings of the National

Academy of Sciences of the United States of America 2002;99(9):

6292–7.

References to other published versions of this review

Davies 2003

Davies HR, Richeldi R, Walters EH. Immunomodulatory agents in

idiopathic pulmonary fibrosis. Cochrane Database of Systematic

Reviews 2003, Issue 3. [DOI: 10.1002/14651858.CD003134]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Azuma 2005

Methods Randomised, double-blind, placebo-controlled trial

Participants Inclusion criteria: either definite HRCT UIP pattern or probable HRCT UIP pattern associated

with presence of other typical clinical features, including bibasilar inspiratory crackles, abnormal

PFTs, and increased serum levels of damaged-pneumocyte markers. Age limit: 20 to 75 years. PaO2

≥ 70 mmHg at rest; SpO2 ≤ 90% during exertion while breathing air, within 1 month before

enrolment.

Exclusion criteria: a decrease in symptoms during the preceding 6 months, use of immunosuppres-

sives and/or oral prednisone greater than 10 mg/day during the preceding 3 months, clinical suspi-

cion of idiopathic interstitial pneumonia other than IPF, coexisting emphysema, pulmonary hyper-

tension, asthma, tuberculosis, sarcoidosis, bronchiectasis other than traction associated, aspergillosis

or respiratory infection; uncontrolled diabetes, comorbid conditions including malignancy, severe

hepatic, renal, or cardiac disease; pregnancy, breastfeeding; previous use of pirfenidone, suspicion

of poor compliance in adherence to protocol, or being unable to understand protocol/written in-

formed consent

Interventions Group A, Treatment: pirfenidone (n = 73)

Group B, Control: placebo (n = 36)

Drug administration: a dose-titration schedule was followed for all patients at a dose of 200 mg 3

times a day for the first 2 days, 400 mg 3 times a day for the 2 following days, and 600 mg 3 times a

day (maximum dose) for the last 3 days. The maximum dose was maintained in patients tolerating

it throughout the study.

Outcomes Primary: change in the lowest SpO2 during a 6-minute steady-state exercise test

Secondary: changes in resting PFTs while breathing air (VC, TLC, DLCO, PaO2), disease progres-

sion by HRCT patterns, episodes of acute exacerbation of IPF, change in KL-6 - a serum marker

of pneumocyte damage - and change in QoL

Notes Two patients were excluded because they had violated the inclusion criteria

Based primarily on important 6-month trends in a secondary endpoint (number of IPF exacer-

bations), the Data and Safety Monitoring Board (DSMB) recommended early termination of the

trial on ethical grounds

Risk of bias

Item Authors’ judgement Description

Adequate sequence generation? Unclear A modified permuted-block randomisation

method with block sizes of 6 was used

Allocation concealment? Unclear Information was not available for this item



Azuma 2005 (Continued)

Blinding?

All outcomes

Yes Investigators were blinded to patients identifi-

cation, treatment assignment and temporal se-

quence of the study. Patients received oral tablets

for pirfenidone or placebo.

Follow-up?

All outcomes

Yes Two patients were excluded due to pre-specifi-

cations because they had violated the inclusion

criteria

BUILD 1

Methods Randomised, multicentre, double-blind, placebo-controlled trial

Participants Inclusion criteria: patients with a proven diagnosis of IPF made within the last 3 years before

enrolment according to the ATS/ERS consensus statement and with a baseline 6MWD between

150 and 499 m

Exclusion criteria: patients with ILD due to conditions other than IPF; FVC < 50% predicted

or of 90% predicted or greater; DLCO < 30% predicted or RV > 120%; FEV1/FVC < 65%;

systolic pulmonary pressure > 50 mm Hg or tricuspid regurgitation velocity > 3.2 m/s; severe

congestive heart failure, or a terminal (expected survival, 1 yr) concomitant illness; PaO2 < 55

mmHg, haemoglobin concentration < 75% of the lower limit of normal; systolic blood pressure <

85 mmHg, moderate to severe hepatic impairment, and serum creatinine of 2.5 mg/dl or greater

Interventions Group A, Treatment: bosentan - a compound with anti-inflammatory and anti-fibrotic properties -

62.5 mg twice daily for 4 weeks, increased to 125 mg twice daily thereafter (n = 71)


Outcomes Primary: change in 6MWD from baseline up to month 12

Secondary: time to death or disease progression, change in PFT and dyspnoea scores, QoL scores

assessed using SF-36 and SGRQ

Notes Concomitant treatment with immunosuppressive, cytotoxic drugs or other investigational agents

was not allowed, except for stable corticosteroid therapy of 15 mg or less of prednisone or equivalent

Risk of bias


Adequate sequence generation? Unclear The trial is described as randomised but the

method used for the allocation sequence gener-

ation is not described

Allocation concealment? Unclear The trial is described as randomised but the

method used to conceal the allocation is not de-

scribed

Blinding?

All outcomes

Yes



BUILD 1 (Continued)

Follow-up?

All outcomes

Yes 154 out 158 randomised patients were included

in the analysis. Withdrawals and dropouts are

described

CAPACITY 1

Methods Randomised, double-blind, placebo-controlled phase III trial

Participants Eligible patients: patients with diagnosis of IPF based on clinical, radiologic, and/or pathologic data

Inclusion criteria: diagnosis of IPF within 48 months of randomisation, clinical symptoms consistent

with IPF of ≥3 months duration, age 40 through 80 years, inclusive, % predicted FVC ≥50% at

the Screen Visit and Day 1 (before randomisation), change in FVC (measured in litres) between the

Screen Visit and Day 1 ≤ 10% relative difference, haemoglobin (Hb)-corrected DLCO ≥35% of

predicted value at the Screen Visit only, FVC or Hb-corrected DLCO ≤90% of predicted value at

the Screen Visit, no evidence of improvement in measures of IPF disease severity over the preceding

year, distance walked ≥150 metres with O2 saturation ≥83% on ≤6 L/min of O2 during the

6MWT oxygen titration procedure performed at the screening visit

Exclusion criteria: candidate unlikely to comply with the study requirements, premature withdrawal

from a randomised IPF clinical trial in the previous 2 years for any reason other than Sponsor

decision, current participation in a clinical drug trial; FEV1/FVC < 0.7 after bronchodilator at

the Screen Visit; absolute increase of ≥ 12% and an increase of 200 ml in FEV1 or FVC or both

after bronchodilator at the Screen Visit; RV > 120% predicted; history of clinically significant

environmental exposure known to cause pulmonary fibrosis; known explanation for interstitial

lung disease; diagnosis of any connective tissue disease; clinical evidence of active infection; patients

expected to need and eligible for a lung transplant within 72 weeks after randomisation; unable

to undergo PFT; any history of malignancy likely to result in death or significant disability or

likely to require significant medical or surgical intervention within the following 2 years; any

condition other than IPF which was likely to result in death within the following 2 years; history of

advanced cirrhosis or clinically significant liver disease; history of unstable or deteriorating cardiac

or pulmonary disease (other than IPF) within the previous 6 months; pregnancy or lactation; history

of alcohol or substance abuse in the past 2 years; history of any condition or habit associated with

altered consciousness and a risk of aspiration in the past 2 years; family or personal history of

long QT syndrome; prior use of pirfenidone. Patients requiring the following therapies within 28

days prior to screening: 1) investigational therapy defined as any drug that has not been approved

for marketing for any indication; 2) any cytotoxic immunosuppressive, cytokine modulating or

endothelin receptor antagonist agents; 3) concomitant medications being used for the treatment

of IPF.

Interventions Group A, Treatment: pirfenidone 2403 mg/day (n = 171)


Study treatment has been escalated over 15 days to the full dose of 9 capsules per day (3 to 267 mg

capsules taken orally TID with food)

Outcomes Primary: absolute change in percent predicted FVC from baseline to week 72

Secondary: time to worsening of IPF, defined as time to acute IPF exacerbation, IPF-related death,

lung transplant or respiratory hospitalisation, whichever comes first; PFS defined as time to the first

occurrence of either of the following: 10% absolute decline in % predicted FVC or 15% absolute

decline in % predicted Hb-corrected DLCO, or death; categorical assessment of absolute change



CAPACITY 1 (Continued)

from baseline to week 72 in % predicted FVC, in dyspnoea, in the % predicted DLCO, in SpO2

measurement observed during the 6MWT, in the HRCT assessment of lung fibrosis, in distance

walked in the 6MWT

Notes Unpublished study - data provided by sponsor (Intermune)

Risk of bias


Adequate sequence generation? Unclear All randomised codes were generated by a statis-

tician independent of the trial

Allocation concealment? Yes Randomisation was performed by using interac-

tive voice-response system

Blinding?

All outcomes

Yes Neither the investigator, other study personnel,

nor the patients knew which study treatment the

patient was receiving. Pirfenidone and placebo

were visually indistinguishable. Packing and la-

belling were identical.

Follow-up?

All outcomes

Yes

CAPACITY 2

Methods Randomised, double-blind, placebo-controlled phase III trial

Participants Inclusion criteria: diagnosis of IPF within 48 months of randomization, clinical symptoms consistent

with IPF of ≥3 months duration, age 40 through 80 years, inclusive, % predicted FVC ≥50% at

the Screen Visit and Day 1 (before randomisation), change in FVC (measured in litres) between the

Screen Visit and Day 1 ≤ 10% relative difference, haemoglobin (Hb)-corrected DLCO ≥35% of

predicted value at the Screen Visit only, FVC or Hb-corrected DLCO ≤90% of predicted value at

the Screen Visit, no evidence of improvement in measures of IPF disease severity over the preceding

year, distance walked ≥150 metres with O2 saturation ≥83% on ≤6 L/min of O2 during the

6MWT oxygen titration procedure performed at the screening visit.

Exclusion criteria: candidate unlikely to comply with the study requirements, premature withdrawal

from a randomised IPF clinical trial in the previous 2 years for any reason other than Sponsor

decision, current participation in a clinical drug trial; FEV1/FVC < 0.7 after bronchodilator at

the Screen Visit; absolute increase of ≥ 12% and an increase of 200 ml in FEV1 or FVC or both

after bronchodilator at the Screen Visit; RV > 120% predicted; history of clinically significant

environmental exposure known to cause pulmonary fibrosis; known explanation for interstitial

lung disease; diagnosis of any connective tissue disease; clinical evidence of active infection; patients

expected to need and eligible for a lung transplant within 72 weeks after randomisation; unable

to undergo PFT; any history of malignancy likely to result in death or significant disability or

likely to require significant medical or surgical intervention within the following 2 years; any

condition other than IPF which was likely to result in death within the following 2 years; history of



CAPACITY 2 (Continued)

advanced cirrhosis or clinically significant liver disease; history of unstable or deteriorating cardiac

or pulmonary disease (other than IPF) within the previous 6 months; pregnancy or lactation; history

of alcohol or substance abuse in the past 2 years; history of any condition or habit associated with

altered consciousness and a risk of aspiration in the past 2 years; family or personal history of

long QT syndrome; prior use of pirfenidone. Patients requiring the following therapies within 28

days prior to screening: 1) investigational therapy defined as any drug that has not been approved

for marketing for any indication; 2) any cytotoxic immunosuppressive, cytokine modulating or

endothelin receptor antagonist agents; 3) concomitant medications being used for the treatment

of IPF.

Interventions Group A, Treatment: pirfenidone 1197 mg/day (n = 174)

Group B, Treatment: pirfenidone 2403 mg/day (n = 174)

Group C, Control: placebo equivalent administered in divided doses TID with food (n = 87)

Study treatment have been escalated over 15 days to the full maintenance dose of 9 capsules per

day (3 capsules taken orally TID with food). Pirfenidone 133 mg capsules have been used for the

1197 mg/day dose. Pirfenidone 267 mg capsules have been used for the 2403 mg/day dose. All

pirfenidone and placebo capsules have been supplied in opaque, hard, white gelatin capsules and

were visually indistinguishable.

Outcomes Primary: absolute change in percent predicted FVC from baseline to Week 72

Secondary: time to worsening of IPF, defined as time to acute IPF exacerbation, IPF-related death,

lung transplant or respiratory hospitalisation, whichever comes first; PFS defined as time to the first

occurrence of either of the following: 10% absolute decline in % predicted FVC or 15% absolute

decline in % predicted Hb-corrected DLCO, or death; categorical assessment of absolute change

from baseline to Week 72 in % predicted FVC, in dyspnoea, in the % predicted DLCO, in SpO2

measurement observed during the 6MWT, in the HRCT assessment of lung fibrosis, in distance

walked in the 6MWT

Notes Unpublished study - data provided by sponsor (Intermune)

Risk of bias


Adequate sequence generation? Unclear All randomised codes were generated by a statis-

tician independent of the trial



Blinding?

All outcomes

Yes Neither the investigator, other study personnel,

nor the patients knew which study treatment the

patient was receiving. Pirfenidone and placebo

were visually indistinguishable. Packing and la-

belling were identical.

Follow-up?

All outcomes

Yes



Daniels 2010

Methods Randomised, multicentre, double-blind, placebo-controlled phase II trial

Participants Inclusion criteria: patients aged 20 to 79 years with diagnosis of IPF between 3 and 36 months

of screening and demonstration of clinical worsening (defined by the occurrence of any one of

the following within the past year: > 10% decrease in % predicted FVC, worsening CXR, or

worsening dyspnoea at rest or on exertion). Diagnosis of IPF was based on clinical, radiographic,

and pathologic consensus criteria. If a definite or probable diagnosis could not be made by HRCT

criteria, patients underwent surgical lung biopsy.

Exclusion criteria: patients who had an alternate explanation for the presence of fibrotic lung disease

or known connective tissue disease. Patients with IPF who had FVC < 55% predicted at screening,

DLCO < 35% predicted at screening, and PaO2< 60 mmHg (sea level) or 55 mmHg (altitude) at rest

on room air. Patients with obstructive lung disease (FEV1/FVC ratio < 0.6; post-bronchodilator or

residual volume > 120% predicted). Women of childbearing potential and breast-feeding women.

Interventions Group A, Treatment: imatinib mesylate (Gleevec) 600 mg (6 tabs) orally once daily (n = 60)


Outcomes Primary: combined measure of disease progression (defined as > 10% decline from baseline FVC)

or death

Secondary: change from baseline at 96 weeks in % predicted DLCO, in the resting ABG assessment

of A-a gradient, in the number of metres walked in a 6-minute walk test, in the Short Form

(36) Health Survey and St. George’s Respiratory Questionnaire assessments, in the modified CRP

(clinical, radiographic, physiologic) score, OS

Notes

Risk of bias


Adequate sequence generation? Unclear Insufficient information was available to deter-

mine how the randomisation process was con-

ducted. Described as randomised.

Allocation concealment? Yes Randomisation was allocated and controlled

centrally using an Interactive Voice Randomisa-

tion System. The treatment and the control were

coded centrally.

Blinding?

All outcomes

Yes The randomisation system allowed for blinding.

Identical capsules packaged in polyethylene bot-

tles.

Follow-up?

All outcomes

Yes More than 90% of the randomised patients were

included in the final analysis. Exclusions and

withdrawals are described.



Douglas 1998

Methods Randomised, multicentre, prospective, unblinded study

Participants Inclusion criteria: conforms to clinical plus either HRCT or histopathologic criteria for the diagno-

sis of idiopathic UIP; baseline tests performed, including pulmonary function, chest radiograph,

serum creatinine, liver function tests, and complete blood count; willing to return for follow-up

examination at 3-month intervals for 1 yr; age 18 yr or older

Exclusion criteria: history of allergy, intolerance, or unwillingness to take either study drug; preg-

nancy, lactation, or women capable of becoming pregnant who were without adequate birth con-

trol; history of chronic asthma and/or treated for asthma within the previous year; diabetes treated

(including dietary therapy) within the previous year; active tuberculosis treated within the previous

year; use of either study drug within the previous 2 months

Interventions Group A, Treatment: colchicine, 0.6 to 1.2 mg/day at the highest dose tolerated (n = 14)

Group B, Control: prednisone, at 60 mg/day for 1 month, then tapered by 10 mg every 2 weeks

to 40 mg/day after 2 months, then tapered further to 40 mg second daily by the end of the third

month, with subsequent doses determined by clinical response (n = 12)

Outcomes Primary: time of the first occurrence of any of the following: death, significant deterioration of

pulmonary function (15% decline in FVC and/or 20% fall in DLCO), intolerance or adverse event

due to the study drug necessitating cessation of the study medication, addition of a second agent

for treatment (except as noted below), and study dropout for any reason

Notes The use of colchicine in the prednisone arm for less than 2 weeks, and of prednisone at less than

20 mg/day for less than 2 weeks in the colchicine arm was permitted for reasons other than as

treatment of IPF

Risk of bias





Allocation concealment? Unclear Insufficient information was available to assess

this item

Blinding?

All outcomes

No Unblinded

Follow-up?

All outcomes

Yes All patients were included in the analysis



IFIGENIA


Participants Inclusion criteria: patients 18 through 75 years of age, diagnosis of IPF, a dyspnoea score of at least

2 on a scale of 0 to 20, VC ≤ 80%, TLC < 90% and DLCO < 80% of the predicted values

Exclusion criteria: patients who had a contraindication to the standard regimen with prednisone or

with a known intolerance to acetylcysteine; treatment with prednisone at a dose of at least 0.5 mg/

kg/day or with azathioprine at a dose of at least 2 mg/kg/day during the month before inclusion,

or treatment with acetylcysteine at a dose of more than 600 mg per day for more than 3 months

in the previous 3 years. Concomitant or pre-existing diseases, abnormalities or treatment at study

entry or in the past with drugs (such as antioxidants and anti-fibrotic drugs) that interfere with the

diagnosis, severity, therapy or prognosis of IPF

Interventions Group A, Treatment: N-acetylcysteine (oral administration in 600 mg effervescent tablets 3 times

daily) plus prednisone and azathioprine (n = 92)

Group B, Control: placebo plus prednisone and azathioprine (n = 90)

Prednisone dose: starting dose, 0.5 mg/kg/day; 0.4 mg/kg/day at month 2; and 0.3 mg/kg/day at

month 3; the dose was progressively reduced to 10 mg per day in months 4, 5 and 6, and this dose

was maintained until month 12)

Azathioprine dose: 2 mg/kg/day

Outcomes Primary: absolute changes in VC and DLCO between baseline and month 12, changes in VC >

10% or 0.2 litre and changes in DLCO > 15% or 1 mmol per minute per kilopascal

Secondary: changes between baseline and 12 months in % predicted value of VC and DLCO,

DLCO/VA (KCO), clinical, radiological and physiological (CRP score), dyspnoea score, maximum

exercise indices, radiographic disease extent, health status according to SGRQ, number of adverse

effects and withdrawals and mortality

Notes Only 85% patients were included in the analysis

Risk of bias


Adequate sequence generation? Yes Randomisation was performed centrally with the

use of a computer-generated randomisation list

Allocation concealment? Unclear Information not available

Blinding?

All outcomes

Yes

Follow-up?

All outcomes

No The authors randomised 182 patients, of whom

27 were excluded from the analysis (12 in the

treatment arm and 15 in the placebo one). Of

the remaining 155 patients, a further 16 were

lost at follow up and not included in the analysis

at 12 months.



INSPIRE

Methods Randomised, multicentre, double-blind, placebo-controlled trial.

Participants Inclusion criteria: patients 40 to 79 years old, with IPF in the past 48 months, with clinical symptoms

for at least 3 months and disease progression in the past 12 months. Additional enrolment criteria:

FVC of 55% to 90% of the predicted value, DLCO of 35% to 90% of the predicted value, distance

of at least 150 m covered during a 6-minute walk

Exclusion criteria: a FEV/FVC less than 0.60, after use of a bronchodilator; residual volume ex-

ceeding 140% of the predicted value before use of a bronchodilator; history of clinically significant

environmental exposure that was known to cause pulmonary fibrosis; diagnosis of any connective

tissue disease; clinical evidence of active infection or any alternative explanation for interstitial lung

disease. Eligible patients could not be on a waiting list for lung transplantation at randomisation.

Interventions Group A, Treatment: interferon gamma-1beta (200 µg) 3 times per week subcutaneously (n = 551)

Group B, Control: placebo (equivalent volume subcutaneously 3 times per week) (n = 275)

Outcomes Primary: OS measured 90 to 96 weeks after enrolment of the 600th patient

Secondary: survival time without lung transplantation, survival days without hospital admission due

to a respiratory diagnosis, change from baseline at week 96 in dyspnoea, in FVC, DLCO, distance

of a 6-minute walk, PFS, acute respiratory decompensation, acute exacerbation of disease.

Notes OS was measured at the second interim analysis because the study was stopped early. Secondary

endpoints were measured at completion of the study (median duration of 77 weeks on treatment)

because the study was stopped early. Change in dyspnoea and distance of a 6-minute walk were

measured to week 96, and for those patients who had not reached the week 96 visit, data were

imputed as per the statistical analysis.

Risk of bias


Adequate sequence generation? Unclear Randomisation code was generated by an inde-

pendent third party statistician



Blinding?

All outcomes

Yes Masking was achieved by use of identically pack-

aged vials containing clear liquid for both the

study drug and placebo

Follow-up?

All outcomes

Yes Overall 99% of enrolled patients completed the

study; 5 patients were lost to follow up, and 4

withdrew consent



Johnson 1989

Methods Prospective randomised trial

Participants Inclusion criteria: participants with previously untreated “fibrosing alveolitis”. Diagnosis was made

on clinical grounds and confirmed “whenever feasible” by OLB. Thirty-three underwent OLB, 2

underwent drill biopsy and one underwent TBB.

Exclusion criteria: patients who had a positive avian precipitin test or a relevant occupational ex-

posure. Pregnancy or wish to have children in the near future; presence of coincidental malignant

disease, diabetes mellitus or active tuberculosis. In addition patients were not eligible if either reg-

imen was contraindicated on clinical grounds.

Interventions Group A, Treatment: cyclophosphamide plus low dose prednisolone (n = 21). Cyclophosphamide

dose according to weight: 70 kg or more, 120 mg/day; 60 to 69 kg, 110 mg/day; less than 60 kg,

100 mg/day. All patients received prednisolone 20 mg on alternate days

Group B, Control: prednisolone alone (n = 22), initially given in high dosage (according to weight)

and reducing to an alternate day maintenance dose: patients weighing 60 kg or more received

prednisolone 60 mg/day for 4 weeks, then reducing by 5 mg/day each week to a maintenance dose

of 20 mg on alternate days; patients weighing less than 60 kg received prednisolone 1 mg/kg for 4

weeks reducing by the same schedule to 20 mg on alternate days

Outcomes Outcome measures were changes in a 6-point breathlessness scale and pulmonary function testing

(FEV1, FVC, TLC, DLCO, KCO and exercise testing with arterial blood gas analysis), changes in

CXR appearance by means of a modified UICC-ILO classification and 7-point scale and OS

Notes Five participants with collagen vascular disorders were enrolled in each arm; there was no subgroup

analysis based upon these parameters

Risk of bias


Adequate sequence generation? Unclear The trial is described as randomised but the method used for the

allocation sequence generation is not described

Allocation concealment? Unclear The trial is described as randomised but the method used to conceal

the allocation is not described

Blinding?

All outcomes

No The trial was unblinded

Follow-up?

All outcomes

Yes All patients were available for follow up



Kubo 2005

Methods Randomised, multicentre, controlled trial

Participants Inclusion criteria: diagnosis of IPF with demonstrated progressive disease deterioration, despite

medical therapy without prednisolone

Exclusion criteria: clinical or serologic evidence of collagen vascular disease, a history of exposure to

known fibrogenic agents, active infection, malignancy, haemoptysis, hypersensitive pneumonitis,

GI bleeding, or ARDS, obvious signs of pre-existing pulmonary embolism, pulmonary hypertension

due to pulmonary thromboembolism, or phlebitis by colour Doppler ultrasonography or enhanced

CT

Interventions Group A, Treatment: anticoagulant therapy (oral warfarin or low molecular weight heparin) plus

prednisolone (n = 31)

Group B, Control: prednisolone (n = 33)

Dose administration: oral prednisolone therapy in both groups was performed initially at a dosage

of 0.5 to 1.0 mg/kg/day for 4 weeks, with subsequent tapering of the dose to 10 to 20 mg/day over

a 1-month period. Warfarin was used for patients in the anticoagulant group at the dose required

to keep the values of the international normalised ratio between 2.0 and 3.0

Outcomes Primary: OS and hospitalisation-free period

Notes All patients were non-smokers

Risk of bias


Adequate sequence generation? Yes Random-number tables were used for simple ran-

domisation

Allocation concealment? Unclear Insufficient information was presented to assess this

item

Blinding?

All outcomes

No

Follow-up?

All outcomes

No Less than 90% of the randomised patients were in-

cluded in the final analysis. However dropouts and

withdrawals are described

Raghu 1991

Methods Randomised, double-blind, placebo-controlled study

Participants Inclusion criteria: diagnosis of IPF supported by lung biopsy, progressive dyspnoea from day of

onset, progressive roentgenographic parenchymal abnormality, 10% or greater decrease in FVC or

TLC, 20% or greater reduction in DLCO



Raghu 1991 (Continued)

Interventions Group A, Treatment: azathioprine plus prednisone; azathioprine dose of 3 mg/kg/day to a maximum

of 200 mg/day for the duration of the trial (n = 14)

Group B, Control: prednisone and placebo (n = 13)

Prednisone dose: in an initial dose of 1.5 mg/kg/day to a maximum of 100 mg/day for the first 2

weeks followed by a fortnightly decrease according to participants tolerance until a maintenance

dose of 20 mg/day or less was reached

Outcomes Primary: improvement in lung function (FVC ≥ 10%, DLCO ≥ 20%, P[A-a]O2 ≥10%)

Secondary: overall survival

Notes

Risk of bias





Allocation concealment? Unclear A similar number of placebo tablets were dis-

pensed to the patients in control arm

Blinding?

All outcomes

Yes

Follow-up?

All outcomes

Yes All patients were available for follow- up

Raghu 2004


Participants Inclusion criteria: FVC 50% to 90% of the predicted value, a carbon monoxide diffusing capacity

(DLCO) ≥25% of the predicted value, and a PaO2 > 55 mmHg while breathing ambient air at

rest

Exclusion criteria: clinically significant exposure to known fibrogenic agents, an alternative cause

of interstitial lung disease, FEV 1 second/FVC < 0.6 after the use of a bronchodilator, a residual

volume > 120% of the predicted value, active infection within 1 week before enrolment, unstable

cardiovascular or neurologic disease, uncontrolled diabetes, pregnancy, lactation, or a likelihood of

death, as predicted by the investigator, within the next year

Interventions Group A, Treatment: interferon gamma-1beta; 200 µg 3 times weekly (n = 162)


Outcomes Primary: progression-free survival (PFS) - defined as the time to disease progression or death

Secondary: change in DLCO, FVC, P(A-a)O2 at rest, the score on the St. George respiratory

questionnaire (SGRQ), the score on the Transition Dyspnea Index, and the extent of lung fibrosis




on high-resolution CT (HRCT). OS, PFS, change in DLCO, FVC, P(A-a)O2, SGRQ, TDI, extent

of lung fibrosis on HRCT

Notes -

Risk of bias


Adequate sequence generation? Unclear The randomisation code was generated by an

external statistician

Allocation concealment? Unclear The study is presented as randomised, but the

method used to conceal is not described

Blinding?

All outcomes

Yes

Follow-up?

All outcomes

Yes Efficacy analysis included all randomised pa-

tients

Raghu 2008


Participants Inclusion criteria: patients with IPF diagnosed within 2 years of screening who had experienced

measurable progression of dyspnoea and either progressive fibrosis on chest radiograph or no im-

provement in lung function. No improvement in lung function was defined as any of the following:

10% or less improvement in % of predicted values in FVC, 15% or less improvement in values in

the diffusing capacity for carbon monoxide of lung corrected for haemoglobin (DLCOHb), or a

10-mm Hg worsening in the P(A-a)O2 with or without exertion.

Exclusion criteria: FVC < 45%, DLCO < 25%, PaO2 < 55 mmHg (room air at rest), or SaO2 <

88 (room air at rest), previous treatment with TNF antagonist, clinically significant comorbidity

diseases or a history of any rheumatologic disease

Interventions Group A, Treatment: etanercept (subcutaneous); 25 mg twice weekly (n = 46)


Outcomes Primary: changes in the percentage of predicted FVC or DLCO, and in the alveolar-to-arterial

oxygen pressure difference (P(A-a)O2) at rest from baseline over 48 weeks

Secondary: change in TLC % predicted, SaO2 (room air at rest), 6MWT, QoL indices, dyspnoea

index, radiographic progression and overall mortality

Notes -

Risk of bias





Adequate sequence generation? Unclear The study is presented as randomised, but the

method of randomisation is not described

Allocation concealment? Unclear The study is presented as randomised, but the

method used to conceal is not described

Blinding?

All outcomes

Yes

Follow-up?

All outcomes

Yes 98% of randomised patients were included in

efficacy analysis. Withdrawals are described.

Taniguchi 2010

Methods Randomised, multicentre, double-blind, placebo-controlled, phase III clinical trial

Participants Inclusion criteria: adults (20 to 75 years old) with IPF diagnosis and meeting the following arterial

oxygen saturation measured by pulse oximetry (SpO2) criteria: 1) O2 desaturation of ≥ 5% differ-

ence between resting SpO2 and the lowest SpO2 during a 6MET, and 2) the lowest SpO2 ≥ 85%

while breathing air during the 6MET

Exclusion criteria: a decrease in symptoms during the preceding 6 months, use of immunosuppres-

sants and/or oral corticosteroids at a dose of more than 10 mg/day during the preceding 3 months,

clinical features of idiopathic interstitial pneumonia other than IPF, evidence of known coexisting

pulmonary hypertension, asthma, tuberculosis, bronchiectasis, aspergillosis or severe respiratory

infection

Interventions Group A, Treatment: pirfenidone high-dose (1800 mg/day) (n = 108)

Group B, Treatment: pirfenidone low-dose (1200 mg/day) (n = 55)

Group C, Control: placebo (n = 104)

Outcomes Primary: change in VC from baseline to week 52

Secondary: PFS time and change in the lowest SpO2 during 6MET. Tertiary endpoints were pul-

monary function tests (PFTs; PaO2, P(A-a)O2 at rest, TLC and DLCO), acute exacerbation, sub-

jective/objective symptoms, and serum levels of KL-6, surfactant protein (SP)-D and SP-A

Notes 97% enrolled patients were deemed eligible for the full analysis set

Risk of bias


Adequate sequence generation? Unclear Patients were allocated with a modified minimi-

sation method including a few steps of random

allocation based on the idea of biased coin design

to balance baseline SpO2

Allocation concealment? Unclear Insufficient information presented to assess this

item



Taniguchi 2010 (Continued)

Blinding?

All outcomes

Yes

Follow-up?

All outcomes

Yes More than 90% of participants randomised were

deemed eligible for the full analysis set

Ziesche 1999

Methods Randomised, unblinded prospective study

Participants Inclusion criteria: histologically evidence of IPF, decrease in lung function of at least 10% during the

12 months before the study began, despite continuous or repeated treatment with glucocorticoids,

other immunosuppressive agents, or both for at least 6 of the 12 months

Exclusion criteria: history of exposure to organic or inorganic dust or drugs known to cause pul-

monary fibrosis and those with connective-tissue diseases or other chronic lung diseases causing

pulmonary fibrosis, patients with end-stage disease

Interventions The patients were initially treated with 50 mg of oral prednisolone per day for 4 weeks, with

subsequent tapering of the dose to 10 mg per day over a 14-day period, regardless of any previous

treatment. If the glucocorticoid treatment was ineffective, the patients were randomly assigned to

either of the following groups:

Group A, Treatment: interferon gamma-1beta 200 µg 3 times weekly plus 7.5 mg of oral prednisolone

daily for 12 months (n = 9)

Group B, Control: prednisolone alone, 7.5 mg daily for 12 months (n = 9). The dose could be

increased to 25 to 50 mg per day in patients who had deterioration of lung function or worsening

symptoms.

Outcomes Lung function (FVC and TLC) at 3, 6, 9 and 12 months; arterial blood gases at 3, 6, 9 and 12

months; transcription of the genes for TGF-b1, connective-tissue growth factor, and interferon

gamma-1beta in transbronchial-biopsy specimens obtained from the same lung segment before and

after 6 months of therapy

Notes -

Risk of bias


Adequate sequence generation? Unclear Information not available

Allocation concealment? Unclear Information not available

Blinding?

All outcomes

No Unblinded, open-label

Follow-up?

All outcomes

Yes All randomised patients were included in the analysis.

Dropouts and withdrawals were described.



ARDS: acute respiratory distress syndrome; CT: computed tomography; CXR: chest X-Ray; DLCO: diffusion lung capacity; FEV1:

forced expiratory volume in one second; FVC: forced vital capacity; GI: gastrointestinal; HRCT: high resolution computed tomog-

raphy; ILD: interstitial lung disease; IPF: idiopathic pulmonary fibrosis; KCO: transfer coefficient for carbon monoxide; m: metres;

OLB: open-lung biopsy; OS: overall survival; P(A-a)O2: resting alveolar-arterial oxygen difference; PFS: progression-free survival;

PFT: pulmonary function tests; QoL: quality of life; RV: residual volume; SaO2: arterial oxygen saturation; SGRQ: St George’s

Respiratory Questionnaire; SpO2: Pulse Oximeter Oxygen Saturation; TBB: transbronchial biopsy; TDI: Transitional Dyspnoea

Index; TID: three times a day; TLC: Total Lung Capacity; TNF: Tumor Necrosis Factor; UIP: usual interstitial pneumonia; VA:

alveolar volume. VC: vital capacity; yr: year; 6MET: 6-minutes steady-state exercise state; 6MWD: 6-minutes walking distance.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Alton 1989 Small prospective open-label controlled trial of cyclosporin in 10 subjects with late stage IPF. Inadequate

statistical data provided for analysis

Antoniou 2006 Open-label study on 50 IPF patients randomly assigned to interferon gamma-1beta plus prednisone or

colchicine plus prednisone

Baughman 1992 Non-randomised uncontrolled open-label trial of the efficacy of intravenous cyclophosphamide added to

prednisone therapy in 33 patients

Behr 1993 Small non-randomised uncontrolled prospective trial in subjects with IPF or systemic sclerosis. Study inves-

tigated levels of and changes in fibroblast chemotactic response following therapy with oral corticosteroids

+/- cyclophosphamide.

Behr 1997 Small non-randomised prospective trial in subjects with IPF (10 patients) or collagen vascular diseases (10

patients). Addition of N-acetylcysteine to pre-existing immunosuppressive therapies compared to no active

treatment.

Brown 1971 Retrospective case series of 5 patients with pulmonary fibrosis of uncertain aetiology and varied histological

pattern, treated with azathioprine at a dose of either 2 or 3 mg/kg/day. Chlorambucil was substituted for

azathioprine in one subject and cyclophosphamide in another. Three subjects improved

Cegla 1974 Retrospective open-label non-randomised case series of D-penicillamine in high dose (3.6 g/day) in 6 patients

with “severe” pulmonary fibrosis. Three out of 6 patients showed improvement after 2 months.

Cegla 1975 Uncontrolled, non-randomised open-label study comparing prednisolone + either azathioprine, D-penicil-

lamine or K-para-aminobenzoate. Only patients with IPF/UIP were included using then current definitions,

with diagnosis confirmed by OLB or autopsy specimens in 14/27.

Azathioprine appeared to produce the greatest improvement in pulmonary function (VC) and D-penicil-

lamine the greatest improvement in gas exchange (PaO2). Insufficient patients were treated with K-para-

aminobenzoate to allow for any assessment of the effectiveness of this agent.

Cegla 1977 Uncontrolled, non-randomised open-label study of therapy with prednisolone +/- either azathioprine or D-

penicillamine in 32 patients. Prednisolone alone had no effect (4 patients), prednisolone and azathioprine

improved VC in 50% of cases (20 patients), and resting PaO2 in 33%. D-penicillamine and prednisolone

improved VC, resting and exercise PaO2 and was felt to be a superior therapy. A further pilot study combining



(Continued)

prednisolone, azathioprine and D-penicillamine was also described in 4 patients.

Cegla 1978 Retrospective case series with 3 different combinations of immunosuppressive agents: prednisolone with

azathioprine, prednisolone with D-penicillamine or prednisolone, D-penicillamine and either azathioprine

or cyclophosphamide.

Collard 2004 Retrospective study of 164 IPF patients treated with corticosteroid and cyclophosphamide or not treated

Costabel 1981 Case series using combinations of prednisolone, D-penicillamine + azathioprine or cyclophosphamide in

15 patients

Dayton 1993 Non-randomised prospective observational trial with intravenous pulse therapy with cyclophosphamide

added to treatment in 12 patients who had failed prednisolone therapy

Douglas 1997 Retrospective case review based study of colchicine with historical prednisone treated controls

Douglas 2000 Retrospective review of treatment of IPF at the Mayo Clinic

Douglas 2001 Retrospective review of survival as a function of oxygen therapy and treatment in 487 patients with IPF at

the Mayo Clinic

Eliasson 1985 Retrospective open-label case review of 8 patients treated with cyclophosphamide following treatment with

prednisone.

Six out of 8 patients suffered serious adverse effects attributable to cyclophosphamide including cyclophos-

phamide-induced pulmonary fibrosis.

Fukazawa 1990 Case report

Fulmer 1978 Double-blind, randomised, placebo-controlled RCT of prednisone + azathioprine versus prednisone +

placebo in 26 patients in the “mid-course” of IPF. Only published in abstract format with minimal clinical

and statistical detail. There were no significant differences reported in any measured or derived parameter.

The study was excluded as there were inadequate data provided in the published abstract.

Garcia 1998 In vitro trial of the effect of cyclosporin A upon the production of pro-inflammatory cytokines in BAL fluid

Goodman 1978 A pilot open-label, uncontrolled study of D-penicillamine therapy in 18 pulmonary fibrosis patients who

had failed treatment with corticosteroids and/or immunosuppressive agents

Goodman 1981 Open-label, uncontrolled, non-randomised study of penicillamine in 18 patients with various forms of

pulmonary fibrosis resistant to corticosteroids

Subjects had a variety of clinical diagnoses

Gross 1973 Small uncontrolled retrospective case series (3 patients) with only one case of IPF included. Treated with

D-penicillamine.

Haslam 1980 Observational study of 51 subjects to determine predictive value of BAL cell counts. Some subjects had

other forms of pulmonary fibrosis.



(Continued)

Homolka 2001 Small-scale open-label non-randomised uncontrolled trial of cyclosporine A in 9 patients

Kalra 2003 Retrospective study of 21 patients treated with interferon gamma-1beta

Kolb 1998 Retrospective open-label, non-randomised study of intermittent pulse dose intravenous cyclophosphamide

+ oral prednisolone in 18 patients previously failing oral prednisolone

Kondoh 2005 Retrospective study of 27 IPF patients treated with prednisone and cyclophosphamide

Liebetrau 1982 Retrospective case series of 58 patients treated with prednisolone and D-penicillamine

Meier-Sydow 1970 Retrospective case series of 6 patients with IPF treated with a variety of immunosuppressive agents including

oral corticosteroids, 6-mercaptopurine, cyclophosphamide and azathioprine.

Meier-Sydow 1975 Retrospective open-label, uncontrolled case series of 8 patients with IPF or sarcoidosis treated with pred-

nisolone and an additional agent in 5 cases, either azathioprine (3 patients) or D-penicillamine (2 patients)

Meier-Sydow 1979 Open-label, uncontrolled, non-randomised long-term study of prednisone + either azathioprine or D-

penicillamine

Meier-Sydow 1990 Non-randomised, unblinded prospective study adding azathioprine or D-penicillamine to prednisone in 26

patients

Meuret 1978 Case study of single patient treated with prednisone, cyclophosphamide and vincristine. Histology not

compatible with IPF by modern criteria.

Meyer 1994 Open-label uncontrolled trial of the effects of N-acetylcysteine upon BAL concentrations of glutathione in

IPF

Meyer 1995 Short-term, open-label, randomised trial of the effects of N-acetylcysteine upon BAL concentrations of

glutathione in IPF patients and normal controls.

Moolman 1991 Small retrospective uncontrolled case series of 10 patients with pulmonary fibrosis of mixed aetiologies. Trial

utilised cyclosporin + prednisone.

Nadrous 2004 Retrospective study of 478 IPF patients treated with angiotensin-converting enzyme inhibitors

O’Donnell 1987 Prospective, uncontrolled, non-randomised trial of effects of cyclophosphamide + prednisone upon BAL

fluid over 6 months

Pereira 2006 Retrospective, open-label, non-randomised study of 82 IPF patients treated with corticosteroids versus

immunosuppressive therapy (cyclophosphamide or azathioprine) for at least 6 months

Peters 1993 Retrospective review of 35 patients treated empirically with colchicine at the Mayo Clinic. Preliminary study

for subsequent trial.



(Continued)

Raghu 1999b Prospective open-label phase II study of the antifibrotic agent pirfenidone in 54 patients with progressive

deterioration despite prednisone +/- immunosuppressive agents

Roig 2010 Prospective non-randomised unblinded study assessing prednisone plus pulsed cyclophosphamide versus

prednisone plus azathioprine in 46 patients with IPF

Rudd 1981 Prospective observational study investigating non-histological features predicting response to therapy and

prognosis in 120 subjects

Rust 1980 Prospective open-label, uncontrolled, non-randomised study investigating the effects of prednisone and

either D-penicillamine or azathioprine in 25 patients over 4 years

Schlehe 1973 Retrospective case series of 6 patients with diffuse IPF treated with oral corticosteroids and azathioprine.

Many of the patients did not appear to have IPF as defined by modern criteria.

Schulz 1978 Three-patient case series using D-penicillamine

Schwartz 1994 Long-term non-randomised prospective observational study of 39 patients treated with cyclophosphamide

+ oral corticosteroid

Selman 1998 Uncontrolled non-randomised prospective study of colchicine and/or penicillamine therapy + prednisone

in 56 patients

Shishido 1992 Case history

Turner-Warwick 1987 Uncontrolled prospective observational study investigating the utility of serial BAL in assessing clinical

progress in 32 subjects

Undurraga 1998 Case series of 17 patients treated with colchicine

Van Oortegem 1994 Retrospective uncontrolled comparison of corticosteroids and cyclophosphamide in 25 patients

Venuta 1993 Short-term open-label study aimed at reducing prednisolone doses with cyclosporin in 10 patients prior to

entry into lung transplantation programme

Weese 1975 Series of 3 patients with worsening pulmonary fibrosis despite corticosteroid therapy. Probably only one

had IPF/UIP by modern criteria. Two patients appeared to stabilise following the addition of azathioprine

whilst the third responded to cyclophosphamide.

Winterbauer 1978 Uncontrolled, prospective open-label trial, adding azathioprine to prednisone in 20 patients of heterogeneous

histological appearance. 60% improved with therapy.

Xaubet 2001 Prospective open-label, non-randomised trial of intervention versus no intervention in 43 patients. Variety

of interventions used including corticosteroids +/- azathioprine or cyclophosphamide.

Ziesche 1996 Uncontrolled open-label pilot trial of interferon gamma-1beta + low dose prednisolone



(Continued)

Zisman 2000 Uncontrolled, non-randomised prospective study of cyclophosphamide in 19 patients failing or not toler-

ating corticosteroid therapy

OLB: open-lung biopsy; BAL: bronchoalveolar lavage

Characteristics of studies awaiting assessment [ordered by study ID]

Characteristics of ongoing studies [ordered by study ID]

ACE-IPF

Trial name or title AntiCoagulant Effectiveness in Idiopathic Pulmonary Fibrosis

Methods Phase III randomised, placebo-controlled

Participants Study design: incomplete

Interventions Warfarin or placebo

Outcomes Time to death, non-bleeding/non-elective hospitalisation, or > 10% drop in forced vital capacity

Starting date 2009

Contact information NHLBI

Notes -

ARTEMIS-IPF

Trial name or title Randomized, Placebo-Controlled Study to Evaluate Safety and Effectiveness of Ambrisentan in IPF

Methods Phase III, randomised, double-blind, placebo controlled, multicentre, safety/efficacy study

Participants Patients with IPF and honeycombing on HRCT scan of less than or equal to 5%; willing and able to have 2

right heart catheterisations performed; able to perform the 6-minute walk test

Interventions Ambrisentan versus placebo

Outcomes Primary outcome measures:

- Time to death or disease (IPF) progression

Secondary outcome measures:

- Proportion of subjects with disease progression or death at 48 weeks



ARTEMIS-IPF (Continued)

Starting date December 2008

Contact information Gliead Sciences

Notes -

BUILD-3

Trial name or title BUILD 3: Bosentan Use in Interstitial Lung Disease

Methods Phase III, randomised, double-blind, placebo-controlled, multicentre, safety/efficacy study

Participants Patients with a diagnosis of IPF by surgical lung biopsy

Interventions Bosentan versus placebo


- Time to occurrence of disease worsening or death up to end of study


- Proportion of patients who experienced either disease worsening or death at 1 year

Starting date November 2006

Contact information Actelion

Notes Preliminary negative results communicated by the sponsor in March 2010

PANTHER-IPF

Trial name or title Evaluating the Effectiveness of Prednisone, Azathioprine, and N-acetylcysteine in People With Idiopathic

Pulmonary Fibrosis


Participants Diagnosis of IPF in the 48 months before study entry, FVC ≥ 50%; DLCO ≥ 30%

Interventions Prednisone + azathioprine + N-acetylcysteine versus N-acetylcysteine alone versus placebo


- Change in serial forced vital capacity


- Time to disease progression

- Acute exacerbations

- Respiratory infections

- Maintained forced vital capacity response



PANTHER-IPF (Continued)

Starting date October 2009


Notes -

STEP-IPF

Trial name or title Sildenafil Trial of Exercise Performance in Idiopathic Pulmonary Fibrosis


Participants Patients with IPF and DLCO < 35%

Interventions Sildenafil versus placebo


- Change in 6-minute walk distance (defined as greater than or equal to 20% improvement or less than 20%

improvement)

Secondary Outcome Measures:

- Change in dyspnoea

- Change in oxygen desaturation measures (time, distance, recovery time) during 6-minute walk test

- Change in forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO)

- Change in quality of life

- Change in 6-minute walk distance

Starting date August 2007


Notes This study has been published on 18 May 2010, while this review was going through peer review. However,

there were no outcomes of interest to include in the meta-analysis and the results of this trial would not

change the conclusions. As such, this trial will be included in any future update.

TOMORROW

Trial name or title Safety And Efficacy of BIBF 1120 in Idiopathic Pulmonary Fibrosis (the TOMORROW trial)

Methods Phase II double-blind, randomised, placebo-controlled

Participants 400 patients with IPF

Interventions 4 dose strategies of BIBF 1120 treatment for 12 months, compared to placebo

Outcomes The primary endpoint is the rate of decline in FVC (expressed in mL per year), evaluated from baseline until

12th month of treatment, compared to placebo.



TOMORROW (Continued)

Starting date August 2007

Contact information Boehringer Ingelheim Germany

Notes -

DLCO: diffusion lung capacity; FVC: forced vital capacity; HRCT: high resolution computed tomography



D A T A A N D A N A L Y S E S

Comparison 1. Interferon gamma-1beta versus placebo

Outcome or subgroup titleNo. of

studies

No. of

participants Statistical method Effect size

1 Overall survival 2 Hazard Ratio (Random, 95% CI) 0.88 [0.47, 1.64]

2 Progression-free survival 1 Peto Odds Ratio (95% CI) Totals not selected

Comparison 2. Pirfenidone versus placebo


studies

No. of


1 Progression-free survival 3 Hazard Ratio (Random, 95% CI) 0.70 [0.56, 0.88]

2 Absolute change VC from

baseline

2 314 Mean Difference (IV, Random, 95% CI) 0.08 [0.03, 0.13]

Comparison 3. Azathioprine & prednisone versus prednisone


studies

No. of


1 Overall survival 1 Peto Odds Ratio (95% CI) Totals not selected

2 % Predicted change FVC at 12

months

1 Mean Difference (IV, Fixed, 95% CI) Totals not selected

Comparison 4. Colchicine versus prednisone


studies

No. of




months




Comparison 5. N-Acetylcysteine & prednisone & azathioprine versus prednisone & azathioprine & placebo


studies

No. of



2 Absolute change VC from

baseline at 12 months


Comparison 6. Anticoagulant therapy & prednisolone versus prednisolone


studies

No. of



Comparison 7. Etanercept versus placebo


studies

No. of




weeks


Comparison 8. Imatinib versus placebo


studies

No. of





weeks




Comparison 9. Bosentan versus placebo


studies

No. of



Analysis 1.1. Comparison 1 Interferon gamma-1beta versus placebo, Outcome 1 Overall survival.

Review: Non-steroid agents for idiopathic pulmonary fibrosis

Comparison: 1 Interferon gamma-1beta versus placebo

Outcome: 1 Overall survival

Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio

(SE) IV,Random,95% CI IV,Random,95% CI

INSPIRE 0.14 (0.2) 58.2 % 1.15 [ 0.78, 1.70 ]

Raghu 2004 -0.51 (0.33) 41.8 % 0.60 [ 0.31, 1.15 ]

Total (95% CI) 100.0 % 0.88 [ 0.47, 1.64 ]

Heterogeneity: Tau2 = 0.14; Chi2 = 2.84, df = 1 (P = 0.09); I2 =65%

Test for overall effect: Z = 0.41 (P = 0.68)

0.01 0.1 1 10 100

Favours IFN gamma-1b Favours placebo

Analysis 1.2. Comparison 1 Interferon gamma-1beta versus placebo, Outcome 2 Progression-free survival.


Comparison: 1 Interferon gamma-1beta versus placebo

Outcome: 2 Progression-free survival

Study or subgroup IFN gamma-1b Placebo Peto Odds Ratio Peto Odds Ratio

n/N n/N Exp[(O-E)/V],Fixed,95% CI Exp[(O-E)/V],Fixed,95% CI

Raghu 2004 74/162 87/168 0.90 [ 0.66, 1.23 ]

0.01 0.1 1 10 100

Favours IFN gamma-1b Favours placebo



Analysis 2.1. Comparison 2 Pirfenidone versus placebo, Outcome 1 Progression-free survival.


Comparison: 2 Pirfenidone versus placebo


Study or subgroup log [Hazard Ratio] Hazard Ratio Weight Hazard Ratio

(SE) IV,Random,95% CI IV,Random,95% CI

CAPACITY 1 -0.17 (0.19) 35.7 % 0.84 [ 0.58, 1.22 ]

CAPACITY 2 -0.45 (0.2) 32.2 % 0.64 [ 0.43, 0.94 ]

Taniguchi 2010 -0.45 (0.2) 32.2 % 0.64 [ 0.43, 0.94 ]

Total (95% CI) 100.0 % 0.70 [ 0.56, 0.88 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 1.40, df = 2 (P = 0.50); I2 =0.0%


0.01 0.1 1 10 100

Favours pirfenidone Favours placebo

Analysis 2.2. Comparison 2 Pirfenidone versus placebo, Outcome 2 Absolute change VC from baseline.


Comparison: 2 Pirfenidone versus placebo

Outcome: 2 Absolute change VC from baseline

Study or subgroup Pirfenidone Placebo Mean Difference Weight Mean Difference

N Mean(SD) N Mean(SD) IV,Random,95% CI IV,Random,95% CI

Azuma 2005 72 -0.03 (0.22) 35 -0.13 (0.19) 32.0 % 0.10 [ 0.02, 0.18 ]

Taniguchi 2010 104 -0.09 (0.204) 103 -0.16 (0.203) 68.0 % 0.07 [ 0.01, 0.13 ]

Total (95% CI) 176 138 100.0 % 0.08 [ 0.03, 0.13 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 0.36, df = 1 (P = 0.55); I2 =0.0%


-0.2 -0.1 0 0.1 0.2

Favours placebo Favours pirfenidone



Analysis 3.1. Comparison 3 Azathioprine & prednisone versus prednisone, Outcome 1 Overall survival.


Comparison: 3 Azathioprine % prednisone versus prednisone


Study or subgroup Aza + Pred Pred Peto Odds Ratio Peto Odds Ratio


Raghu 1991 6/14 10/13 0.26 [ 0.13, 0.52 ]

0.01 0.1 1 10 100

Favours azathioprine+pred Favours pred

Analysis 3.2. Comparison 3 Azathioprine & prednisone versus prednisone, Outcome 2 % Predicted change

FVC at 12 months.


Comparison: 3 Azathioprine % prednisone versus prednisone

Outcome: 2 % Predicted change FVC at 12 months

Study or subgroup Aza + pred pred Mean Difference Mean Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Raghu 1991 10 6.5 (16.8) 9 1.7 (22.2) 4.80 [ -13.05, 22.65 ]

-100 -50 0 50 100

Favours pred Favours azathioprine+pred



Analysis 4.1. Comparison 4 Colchicine versus prednisone, Outcome 1 Progression-free survival.


Comparison: 4 Colchicine versus prednisone


Study or subgroup Colchicine Prednisone Peto Odds Ratio Peto Odds Ratio


Douglas 1998 9/14 10/12 0.48 [ 0.19, 1.18 ]

0.01 0.1 1 10 100

Favours colchicine Favours prednisone

Analysis 4.2. Comparison 4 Colchicine versus prednisone, Outcome 2 % Predicted change FVC at 3 months.


Comparison: 4 Colchicine versus prednisone

Outcome: 2 % Predicted change FVC at 3 months

Study or subgroup Colchicine Prednisone Mean Difference Mean Difference


Douglas 1998 13 -5.1 (7.7) 11 -6.9 (6.8) 1.80 [ -4.00, 7.60 ]

-10 -5 0 5 10

Favours prednisone Favours colchicine



Analysis 5.1. Comparison 5 N-Acetylcysteine & prednisone & azathioprine versus prednisone &

azathioprine & placebo, Outcome 1 Overall survival.


Comparison: 5 N-Acetylcysteine % prednisone % azathioprine versus prednisone % azathioprine % placebo


Study or subgroup NAC+pred+aza Pred+aza+plac Peto Odds Ratio Peto Odds Ratio


IFIGENIA 7/80 8/80 0.81 [ 0.30, 2.24 ]

0.01 0.1 1 10 100

Favours NAC+pred+aza Favours Pred+aza+plac

Analysis 5.2. Comparison 5 N-Acetylcysteine & prednisone & azathioprine versus prednisone &

azathioprine & placebo, Outcome 2 Absolute change VC from baseline at 12 months.


Comparison: 5 N-Acetylcysteine % prednisone % azathioprine versus prednisone % azathioprine % placebo

Outcome: 2 Absolute change VC from baseline at 12 months

Study or subgroup NAC+pred+aza Pred+aza+plac Mean Difference Mean Difference


IFIGENIA 71 -0.06 (0.34) 68 -0.19 (0.41) 0.13 [ 0.00, 0.26 ]

-1 -0.5 0 0.5 1

Favours pred+aza+plac Favours NAC+pred+aza



Analysis 6.1. Comparison 6 Anticoagulant therapy & prednisolone versus prednisolone, Outcome 1 Overall

survival.


Comparison: 6 Anticoagulant therapy % prednisolone versus prednisolone


Study or subgroup Anticoag % Prednisolone Prednisolone Peto Odds Ratio Peto Odds Ratio


Kubo 2005 5/23 20/33 0.34 [ 0.12, 0.97 ]

0.1 0.2 0.5 1 2 5 10

Favours anticoag + pred Favours pred

Analysis 7.1. Comparison 7 Etanercept versus placebo, Outcome 1 Progression-free survival.


Comparison: 7 Etanercept versus placebo


Study or subgroup Etanercept Placebo Peto Odds Ratio Peto Odds Ratio


Raghu 2008 15/45 22/40 0.61 [ 0.32, 1.17 ]

0.2 0.5 1 2 5

Favours etanercept Favours placebo



Analysis 7.2. Comparison 7 Etanercept versus placebo, Outcome 2 % Predicted change FVC at 48 weeks.


Comparison: 7 Etanercept versus placebo

Outcome: 2 % Predicted change FVC at 48 weeks

Study or subgroup Etanercept Placebo Mean Difference Mean Difference


Raghu 2008 34 -0.1 (0.3) 31 -0.2 (0.3) 0.10 [ -0.05, 0.25 ]

-1 -0.5 0 0.5 1

Favours placebo Favours etanercept

Analysis 8.1. Comparison 8 Imatinib versus placebo, Outcome 1 Progression-free survival.


Comparison: 8 Imatinib versus placebo


Study or subgroup Imatinib Placebo Peto Odds Ratio Peto Odds Ratio


Daniels 2010 0/59 0/60 1.05 [ 0.56, 1.96 ]

0.2 0.5 1 2 5

Favours imatinib Favours placebo



Analysis 8.2. Comparison 8 Imatinib versus placebo, Outcome 2 Overall survival.




Study or subgroup Imatinib Placebo Peto Odds Ratio Peto Odds Ratio


Daniels 2010 8/59 10/60 0.80 [ 0.32, 2.02 ]

0.2 0.5 1 2 5

Favours imatinib Favours placebo

Analysis 8.3. Comparison 8 Imatinib versus placebo, Outcome 3 % Predicted change FVC at 96 weeks.



Outcome: 3 % Predicted change FVC at 96 weeks

Study or subgroup Imatinib Placebo Mean Difference Mean Difference


Daniels 2010 26 -0.25 (0.3) 31 -0.18 (0.34) -0.07 [ -0.24, 0.10 ]

-1 -0.5 0 0.5 1

Favours placebo Favours imatinib



Analysis 9.1. Comparison 9 Bosentan versus placebo, Outcome 1 Progression-free survival.


Comparison: 9 Bosentan versus placebo


Study or subgroup Bosentan Placebo Peto Odds Ratio Peto Odds Ratio


BUILD 1 16/71 30/83 0.61 [ 0.33, 1.14 ]

0.01 0.1 1 10 100

Favours bosentan favours placebo

W H A T ’ S N E W

Last assessed as up-to-date: 26 July 2010.

Date Event Description

27 July 2010 New citation required and conclusions have changed New studies included, conclusions of review changed. Twelve

studies were added to the review. Fifteen trials assessing 10 dif-

ferent drugs are now included. Unpublished data have been

incorporated. Outcomes of the review have been changed to

overall survival and progression-free survival.

27 July 2010 New search has been performed New search for update.

H I S T O R Y

Protocol first published: Issue 2, 2000

Review first published: Issue 3, 2003

Date Event Description

30 September 2008 Amended Converted to new review format.

2 January 2003 New citation required and conclusions have changed Substantive amendment.



C O N T R I B U T I O N S O F A U T H O R S

Paolo Spagnolo: analysis and interpretation of data, drafting the review or commenting on it critically for intellectual content.

Cinzia Del Giovane: analysis and interpretation of data, drafting the review or commenting on it critically for intellectual content.

Fabrizio Luppi: analysis and interpretation of data, drafting the review or commenting on it critically for intellectual content.

Stefania Cerri: analysis and interpretation of data, drafting the review or commenting on it critically for intellectual content.

Sara Balduzzi: analysis and interpretation of data.

E. Haydn Walters: drafting of current review document; comment on intellectual content; editing of previous review.

Huw Davies: contribution to the first version of the review.

Roberto D’Amico: analysis and interpretation of data, drafting the review or commenting on it critically for intellectual content.

Luca Richeldi: conception and design of study, drafting the review or commenting on it critically for intellectual content, final approval

of the document to be published.

D E C L A R A T I O N S O F I N T E R E S T

Luca Richeldi acted as global principal investigator and steering committee member in an IPF trial sponsored by Boehringer Ingelheim

(Germany); he has been a consultant in IPF-related studies with Celgene (USA), Gilead (USA), Novartis (Switzerland), Actelion

(France), Genzyme (USA) and Mondobiotech (Switzerland); he has been principal investigator of a clinical site participating in the

INSPIRE and CAPACITY 2 trials, both sponsored by Intermune (USA), in the ARTEMIS trial, sponsored by Gilead (USA) and in

the TOMORROW trial, sponsored by Boehringer Ingelheim (Germany). Other authors report no potential conflicts of interest with

the subject of this review.

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

Risk of bias has been updated using current methods and the outcomes have been revised to reflect survival measures and lung function.

N O T E S

None.

I N D E X T E R M SMedical Subject Headings (MeSH)

Anti-Inflammatory Agents, Non-Steroidal [therapeutic use]; Azathioprine [therapeutic use]; Colchicine [therapeutic use]; Cyclophos-

phamide [therapeutic use]; Immunosuppressive Agents [∗therapeutic use]; Interferon-gamma, Recombinant [therapeutic use]; Pred-

nisone [therapeutic use]; Pulmonary Fibrosis [∗drug therapy]; Pyridones [therapeutic use]; Randomized Controlled Trials as Topic



MeSH check words

Humans



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